Nineteen Eighty-Four – Wikipedia

Nineteen Eighty-Four, often published as 1984, is a dystopian novel published in 1949 by English author George Orwell.[2][3] The novel is set in the year 1984 when most of the world population have become victims of perpetual war, omnipresent government surveillance and public manipulation.

In the novel, Great Britain (“Airstrip One”) has become a province of a superstate named Oceania. Oceania is ruled by the “Party”, who employ the “Thought Police” to persecute individualism and independent thinking.[4] The Party’s leader is Big Brother, who enjoys an intense cult of personality but may not even exist. The protagonist of the novel, Winston Smith, is a rank-and-file Party member. Smith is an outwardly diligent and skillful worker, but he secretly hates the Party and dreams of rebellion against Big Brother. Smith rebels by entering a forbidden relationship with fellow employee Julia.

As literary political fiction and dystopian science-fiction, Nineteen Eighty-Four is a classic novel in content, plot, and style. Many of its terms and concepts, such as Big Brother, doublethink, thoughtcrime, Newspeak, Room 101, telescreen, 2 + 2 = 5, and memory hole, have entered into common usage since its publication in 1949. Nineteen Eighty-Four popularised the adjective Orwellian, which describes official deception, secret surveillance, brazenly misleading terminology, and manipulation of recorded history by a totalitarian or authoritarian state.[5] In 2005, the novel was chosen by Time magazine as one of the 100 best English-language novels from 1923 to 2005.[6] It was awarded a place on both lists of Modern Library 100 Best Novels, reaching number 13 on the editor’s list, and 6 on the readers’ list.[7] In 2003, the novel was listed at number 8 on the BBC’s survey The Big Read.[8]

Orwell “encapsulate[d] the thesis at the heart of his unforgiving novel” in 1944, the implications of dividing the world up into zones of influence, which had been conjured by the Tehran Conference. Three years later, he wrote most of it on the Scottish island of Jura from 1947 to 1948 despite being seriously ill with tuberculosis.[9][10] On 4 December 1948, he sent the final manuscript to the publisher Secker and Warburg, and Nineteen Eighty-Four was published on 8 June 1949.[11][12] By 1989, it had been translated into 65 languages, more than any other novel in English until then.[13] The title of the novel, its themes, the Newspeak language and the author’s surname are often invoked against control and intrusion by the state, and the adjective Orwellian describes a totalitarian dystopia that is characterised by government control and subjugation of the people.

Orwell’s invented language, Newspeak, satirises hypocrisy and evasion by the state: the Ministry of Love (Miniluv) oversees torture and brainwashing, the Ministry of Plenty (Miniplenty) oversees shortage and rationing, the Ministry of Peace (Minipax) oversees war and atrocity and the Ministry of Truth (Minitrue) oversees propaganda and historical revisionism.

The Last Man in Europe was an early title for the novel, but in a letter dated 22 October 1948 to his publisher Fredric Warburg, eight months before publication, Orwell wrote about hesitating between that title and Nineteen Eighty-Four.[14] Warburg suggested choosing the main title to be the latter, a more commercial one.[15]

In the novel 1985 (1978), Anthony Burgess suggests that Orwell, disillusioned by the onset of the Cold War (194591), intended to call the book 1948. The introduction to the Penguin Books Modern Classics edition of Nineteen Eighty-Four reports that Orwell originally set the novel in 1980 but that he later shifted the date to 1982 and then to 1984. The introduction to the Houghton Mifflin Harcourt edition of Animal Farm and 1984 (2003) reports that the title 1984 was chosen simply as an inversion of the year 1948, the year in which it was being completed, and that the date was meant to give an immediacy and urgency to the menace of totalitarian rule.[16]

Throughout its publication history, Nineteen Eighty-Four has been either banned or legally challenged, as subversive or ideologically corrupting, like Aldous Huxley’s Brave New World (1932), We (1924) by Yevgeny Zamyatin, Darkness at Noon (1940) by Arthur Koestler, Kallocain (1940) by Karin Boye and Fahrenheit 451 (1953) by Ray Bradbury.[17] Some writers consider the Russian dystopian novel We by Zamyatin to have influenced Nineteen Eighty-Four,[18][19] and the novel bears significant similarities in its plot and characters to Darkness at Noon, written years before by Arthur Koestler, who was a personal friend of Orwell.[20]

The novel is in the public domain in Canada,[21] South Africa,[22] Argentina,[23] Australia,[24] and Oman.[25] It will be in the public domain in the United Kingdom, the EU,[26] and Brazil in 2021[27] (70 years after the author’s death), and in the United States in 2044.[28]

Nineteen Eighty-Four is set in Oceania, one of three inter-continental superstates that divided the world after a global war.

Smith’s memories and his reading of the proscribed book, The Theory and Practice of Oligarchical Collectivism by Emmanuel Goldstein, reveal that after the Second World War, the United Kingdom became involved in a war fought in Europe, western Russia, and North America during the early 1950s. Nuclear weapons were used during the war, leading to the destruction of Colchester. London would also suffer widespread aerial raids, leading Winston’s family to take refuge in a London Underground station. Britain fell to civil war, with street fighting in London, before the English Socialist Party, abbreviated as Ingsoc, emerged victorious and formed a totalitarian government in Britain. The British Commonwealth was absorbed by the United States to become Oceania. Eventually Ingsoc emerged to form a totalitarian government in the country.

Simultaneously, the Soviet Union conquered continental Europe and established the second superstate of Eurasia. The third superstate of Eastasia would emerge in the Far East after several decades of fighting. The three superstates wage perpetual war for the remaining unconquered lands of the world in “a rough quadrilateral with its corners at Tangier, Brazzaville, Darwin, and Hong Kong” through constantly shifting alliances. Although each of the three states are said to have sufficient natural resources, the war continues in order to maintain ideological control over the people.

However, due to the fact that Winston barely remembers these events and due to the Party’s manipulation of history, the continuity and accuracy of these events are unclear. Winston himself notes that the Party has claimed credit for inventing helicopters, airplanes and trains, while Julia theorizes that the perpetual bombing of London is merely a false-flag operation designed to convince the populace that a war is occurring. If the official account was accurate, Smith’s strengthening memories and the story of his family’s dissolution suggest that the atomic bombings occurred first, followed by civil war featuring “confused street fighting in London itself” and the societal postwar reorganisation, which the Party retrospectively calls “the Revolution”.

Most of the plot takes place in London, the “chief city of Airstrip One”, the Oceanic province that “had once been called England or Britain”.[29][30] Posters of the Party leader, Big Brother, bearing the caption “BIG BROTHER IS WATCHING YOU”, dominate the city (Winston states it can be found on nearly every house), while the ubiquitous telescreen (transceiving television set) monitors the private and public lives of the populace. Military parades, propaganda films, and public executions are said to be commonplace.

The class hierarchy of Oceania has three levels:

As the government, the Party controls the population with four ministries:

The protagonist Winston Smith, a member of the Outer Party, works in the Records Department of the Ministry of Truth as an editor, revising historical records, to make the past conform to the ever-changing party line and deleting references to unpersons, people who have been “vaporised”, i.e., not only killed by the state but denied existence even in history or memory.

The story of Winston Smith begins on 4 April 1984: “It was a bright cold day in April, and the clocks were striking thirteen.” Yet he is uncertain of the true date, given the regime’s continual rewriting and manipulation of history.[31]

In the year 1984, civilization has been damaged by war, civil conflict, and revolution. Airstrip One (formerly Britain) is a province of Oceania, one of the three totalitarian super-states that rules the world. It is ruled by the “Party” under the ideology of “Ingsoc” and the mysterious leader Big Brother, who has an intense cult of personality. The Party stamps out anyone who does not fully conform to their regime using the Thought Police and constant surveillance, through devices such as Telescreens (two-way televisions).

Winston Smith is a member of the middle class Outer Party. He works at the Ministry of Truth, where he rewrites historical records to conform to the state’s ever-changing version of history. Those who fall out of favour with the Party become “unpersons”, disappearing with all evidence of their existence removed. Winston revises past editions of The Times, while the original documents are destroyed by fire in a “memory hole”. He secretly opposes the Party’s rule and dreams of rebellion. He realizes that he is already a “thoughtcriminal” and likely to be caught one day.

While in a proletarian neighbourhood, he meets an antique shop owner called Mr. Charrington and buys a diary. He uses an alcove to hide it from the Telescreen in his room, and writes thoughts criticising the Party and Big Brother. In the journal, he records his sexual frustration over a young woman maintaining the novel-writing machines at the ministry named Julia, whom Winston is attracted to but suspects is an informant. He also suspects that his superior, an Inner Party official named O’Brien, is a secret agent for an enigmatic underground resistance movement known as the Brotherhood, a group formed by Big Brother’s reviled political rival Emmanuel Goldstein.

The next day, Julia secretly hands Winston a note confessing her love for him. Winston and Julia begin an affair, an act of the rebellion as the Party insists that sex may only be used for reproduction. Winston realizes that she shares his loathing of the Party. They first meet in the country, and later in a rented room above Mr. Charrington’s shop. During his affair with Julia, Winston remembers the disappearance of his family during the civil war of the 1950s and his terse relationship with his ex-wife Katharine. Winston also interacts with his colleague Syme, who is writing a dictionary for a revised version of the English language called Newspeak. After Syme admits that the true purpose of Newspeak is to reduce the capacity of human thought, Winston speculates that Syme will disappear. Not long after, Syme disappears and no one acknowledges his absence.

Weeks later, Winston is approached by O’Brien, who offers Winston a chance to join the Brotherhood. They arrange a meeting at O’Brien’s luxurious flat where both Winston and Julia swear allegiance to the Brotherhood. He sends Winston a copy of The Theory and Practice of Oligarchical Collectivism by Emmanuel Goldstein. Winston and Julia read parts of the book, which explains more about how the Party maintains power, the true meanings of its slogans and the concept of perpetual war. It argues that the Party can be overthrown if proles (proletarians) rise up against it.

Mr. Charrington is revealed to be an agent of the Thought Police. Winston and Julia are captured in the shop and imprisoned in the Ministry of Love. O’Brien reveals that he is loyal to the party, and part of a special sting operation to catch “thoughtcriminals”. Over many months, Winston is tortured and forced to “cure” himself of his “insanity” by changing his own perception to fit the Party line, even if it requires saying that “2 + 2 = 5”. O’Brien openly admits that the Party “is not interested in the good of others; it is interested solely in power.” He says that once Winston is brainwashed into loyalty, he will be released back into society for a period of time, before they execute him. Winston points out that the Party has not managed to make him betray Julia.

O’Brien then takes Winston to Room 101 for the final stage of re-education. The room contains each prisoner’s worst fear, in Winston’s case rats. As a wire cage holding hungry rats is fitted onto his face, Winston shouts “Do it to Julia!”, thus betraying her. After being released, Winston meets Julia in a park. She says that she was also tortured, and both reveal betraying the other. Later, Winston sits alone in a caf as Oceania celebrates a supposed victory over Eurasian armies in Africa, and realizes that “He loved Big Brother.”

Ingsoc (English Socialism) is the predominant ideology and pseudophilosophy of Oceania, and Newspeak is the official language of official documents.

In London, the capital city of Airstrip One, Oceania’s four government ministries are in pyramids (300 m high), the faades of which display the Party’s three slogans. The ministries’ names are the opposite (doublethink) of their true functions: “The Ministry of Peace concerns itself with war, the Ministry of Truth with lies, the Ministry of Love with torture and the Ministry of Plenty with starvation.” (Part II, Chapter IX The Theory and Practice of Oligarchical Collectivism)

The Ministry of Peace supports Oceania’s perpetual war against either of the two other superstates:

The primary aim of modern warfare (in accordance with the principles of doublethink, this aim is simultaneously recognized and not recognized by the directing brains of the Inner Party) is to use up the products of the machine without raising the general standard of living. Ever since the end of the nineteenth century, the problem of what to do with the surplus of consumption goods has been latent in industrial society. At present, when few human beings even have enough to eat, this problem is obviously not urgent, and it might not have become so, even if no artificial processes of destruction had been at work.

The Ministry of Plenty rations and controls food, goods, and domestic production; every fiscal quarter, it publishes false claims of having raised the standard of living, when it has, in fact, reduced rations, availability, and production. The Ministry of Truth substantiates Ministry of Plenty’s claims by revising historical records to report numbers supporting the current, “increased rations”.

The Ministry of Truth controls information: news, entertainment, education, and the arts. Winston Smith works in the Minitrue RecDep (Records Department), “rectifying” historical records to concord with Big Brother’s current pronouncements so that everything the Party says is true.

The Ministry of Love identifies, monitors, arrests, and converts real and imagined dissidents. In Winston’s experience, the dissident is beaten and tortured, and, when near-broken, he is sent to Room 101 to face “the worst thing in the world”until love for Big Brother and the Party replaces dissension.

The keyword here is blackwhite. Like so many Newspeak words, this word has two mutually contradictory meanings. Applied to an opponent, it means the habit of impudently claiming that black is white, in contradiction of the plain facts. Applied to a Party member, it means a loyal willingness to say that black is white when Party discipline demands this. But it means also the ability to believe that black is white, and more, to know that black is white, and to forget that one has ever believed the contrary. This demands a continuous alteration of the past, made possible by the system of thought which really embraces all the rest, and which is known in Newspeak as doublethink. Doublethink is basically the power of holding two contradictory beliefs in one’s mind simultaneously, and accepting both of them.

Three perpetually warring totalitarian super-states control the world:[34]

The perpetual war is fought for control of the “disputed area” lying “between the frontiers of the super-states”, which forms “a rough parallelogram with its corners at Tangier, Brazzaville, Darwin and Hong Kong”,[34] and Northern Africa, the Middle East, India and Indonesia are where the superstates capture and use slave labour. Fighting also takes place between Eurasia and Eastasia in Manchuria, Mongolia and Central Asia, and all three powers battle one another over various Atlantic and Pacific islands.

Goldstein’s book, The Theory and Practice of Oligarchical Collectivism, explains that the superstates’ ideologies are alike and that the public’s ignorance of this fact is imperative so that they might continue believing in the detestability of the opposing ideologies. The only references to the exterior world for the Oceanian citizenry (the Outer Party and the Proles) are Ministry of Truth maps and propaganda to ensure their belief in “the war”.

Winston Smith’s memory and Emmanuel Goldstein’s book communicate some of the history that precipitated the Revolution. Eurasia was formed when the Soviet Union conquered Continental Europe, creating a single state stretching from Portugal to the Bering Strait. Eurasia does not include the British Isles because the United States annexed them along with the rest of the British Empire and Latin America, thus establishing Oceania and gaining control over a quarter of the planet. Eastasia, the last superstate established, emerged only after “a decade of confused fighting”. It includes the Asian lands conquered by China and Japan. Although Eastasia is prevented from matching Eurasia’s size, its larger populace compensates for that handicap.

The annexation of Britain occurred about the same time as the atomic war that provoked civil war, but who fought whom in the war is left unclear. Nuclear weapons fell on Britain; an atomic bombing of Colchester is referenced in the text. Exactly how Ingsoc and its rival systems (Neo-Bolshevism and Death Worship) gained power in their respective countries is also unclear.

While the precise chronology cannot be traced, most of the global societal reorganization occurred between 1945 and the early 1960s. Winston and Julia once meet in the ruins of a church that was destroyed in a nuclear attack “thirty years” earlier, which suggests 1954 as the year of the atomic war that destabilised society and allowed the Party to seize power. It is stated in the novel that the “fourth quarter of 1983” was “also the sixth quarter of the Ninth Three-Year Plan”, which implies that the first quarter of the first three-year plan began in July 1958. By then, the Party was apparently in control of Oceania.

In 1984, there is a perpetual war between Oceania, Eurasia and Eastasia, the superstates that emerged from the global atomic war. The Theory and Practice of Oligarchical Collectivism, by Emmanuel Goldstein, explains that each state is so strong it cannot be defeated, even with the combined forces of two superstates, despite changing alliances. To hide such contradictions, history is rewritten to explain that the (new) alliance always was so; the populaces are accustomed to doublethink and accept it. The war is not fought in Oceanian, Eurasian or Eastasian territory but in the Arctic wastes and in a disputed zone comprising the sea and land from Tangiers (Northern Africa) to Darwin (Australia). At the start, Oceania and Eastasia are allies fighting Eurasia in northern Africa and the Malabar Coast.

That alliance ends and Oceania, allied with Eurasia, fights Eastasia, a change occurring on Hate Week, dedicated to creating patriotic fervour for the Party’s perpetual war. The public are blind to the change; in mid-sentence, an orator changes the name of the enemy from “Eurasia” to “Eastasia” without pause. When the public are enraged at noticing that the wrong flags and posters are displayed, they tear them down; the Party later claims to have captured Africa.

Goldstein’s book explains that the purpose of the unwinnable, perpetual war is to consume human labour and commodities so that the economy of a superstate cannot support economic equality, with a high standard of life for every citizen. By using up most of the produced objects like boots and rations, the proles are kept poor and uneducated and will neither realise what the government is doing nor rebel. Goldstein also details an Oceanian strategy of attacking enemy cities with atomic rockets before invasion but dismisses it as unfeasible and contrary to the war’s purpose; despite the atomic bombing of cities in the 1950s, the superstates stopped it for fear that would imbalance the powers. The military technology in the novel differs little from that of World War II, but strategic bomber aeroplanes are replaced with rocket bombs, helicopters were heavily used as weapons of war (they did not figure in World War II in any form but prototypes) and surface combat units have been all but replaced by immense and unsinkable Floating Fortresses, island-like contraptions concentrating the firepower of a whole naval task force in a single, semi-mobile platform (in the novel, one is said to have been anchored between Iceland and the Faroe Islands, suggesting a preference for sea lane interdiction and denial).

The society of Airstrip One and, according to “The Book”, almost the whole world, lives in poverty: hunger, disease and filth are the norms. Ruined cities and towns are common: the consequence of the civil war, the atomic wars and the purportedly enemy (but possibly false flag) rockets. Social decay and wrecked buildings surround Winston; aside from the ministerial pyramids, little of London was rebuilt. Members of the Outer Party consume synthetic foodstuffs and poor-quality “luxuries” such as oily gin and loosely-packed cigarettes, distributed under the “Victory” brand. (That is a parody of the low-quality Indian-made “Victory” cigarettes, widely smoked in Britain and by British soldiers during World War II. They were smoked because it was easier to import them from India than it was to import American cigarettes from across the Atlantic because of the War of the Atlantic.)

Winston describes something as simple as the repair of a broken pane of glass as requiring committee approval that can take several years and so most of those living in one of the blocks usually do the repairs themselves (Winston himself is called in by Mrs. Parsons to repair her blocked sink). All Outer Party residences include telescreens that serve both as outlets for propaganda and to monitor the Party members; they can be turned down, but they cannot be turned off.

In contrast to their subordinates, the Inner Party upper class of Oceanian society reside in clean and comfortable flats in their own quarter of the city, with pantries well-stocked with foodstuffs such as wine, coffee and sugar, all denied to the general populace.[35] Winston is astonished that the lifts in O’Brien’s building work, the telescreens can be switched off and O’Brien has an Asian manservant, Martin. All members of the Inner Party are attended to by slaves captured in the disputed zone, and “The Book” suggests that many have their own motorcars or even helicopters. Nonetheless, “The Book” makes clear that even the conditions enjoyed by the Inner Party are only “relatively” comfortable, and standards would be regarded as austere by those of the prerevolutionary lite.[36]

The proles live in poverty and are kept sedated with alcohol, pornography and a national lottery whose winnings are never actually paid out; that is obscured by propaganda and the lack of communication within Oceania. At the same time, the proles are freer and less intimidated than the middle-class Outer Party: they are subject to certain levels of monitoring but are not expected to be particularly patriotic. They lack telescreens in their own homes and often jeer at the telescreens that they see. “The Book” indicates that is because the middle class, not the lower class, traditionally starts revolutions. The model demands tight control of the middle class, with ambitious Outer-Party members neutralised via promotion to the Inner Party or “reintegration” by the Ministry of Love, and proles can be allowed intellectual freedom because they lack intellect. Winston nonetheless believes that “the future belonged to the proles”.[37]

The standard of living of the populace is low overall. Consumer goods are scarce, and all those available through official channels are of low quality; for instance, despite the Party regularly reporting increased boot production, more than half of the Oceanian populace goes barefoot. The Party claims that poverty is a necessary sacrifice for the war effort, and “The Book” confirms that to be partially correct since the purpose of perpetual war consumes surplus industrial production. Outer Party members and proles occasionally gain access to better items in the market, which deals in goods that were pilfered from the residences of the Inner Party.[citation needed]

Nineteen Eighty-Four expands upon the subjects summarised in Orwell’s essay “Notes on Nationalism”[38] about the lack of vocabulary needed to explain the unrecognised phenomena behind certain political forces. In Nineteen Eighty-Four, the Party’s artificial, minimalist language ‘Newspeak’ addresses the matter.

O’Brien concludes: “The object of persecution is persecution. The object of torture is torture. The object of power is power.”

In the book, Inner Party member O’Brien describes the Party’s vision of the future:

There will be no curiosity, no enjoyment of the process of life. All competing pleasures will be destroyed. But alwaysdo not forget this, Winstonalways there will be the intoxication of power, constantly increasing and constantly growing subtler. Always, at every moment, there will be the thrill of victory, the sensation of trampling on an enemy who is helpless. If you want a picture of the future, imagine a boot stamping on a human faceforever.

Part III, Chapter III, Nineteen Eighty-Four

A major theme of Nineteen Eighty-Four is censorship, especially in the Ministry of Truth, where photographs are modified and public archives rewritten to rid them of “unpersons” (persons who are erased from history by the Party). On the telescreens, figures for all types of production are grossly exaggerated or simply invented to indicate an ever-growing economy, when the reality is the opposite. One small example of the endless censorship is Winston being charged with the task of eliminating a reference to an unperson in a newspaper article. He proceeds to write an article about Comrade Ogilvy, a made-up party member who displayed great heroism by leaping into the sea from a helicopter so that the dispatches he was carrying would not fall into enemy hands.

The inhabitants of Oceania, particularly the Outer Party members, have no real privacy. Many of them live in apartments equipped with two-way telescreens so that they may be watched or listened to at any time. Similar telescreens are found at workstations and in public places, along with hidden microphones. Written correspondence is routinely opened and read by the government before it is delivered. The Thought Police employ undercover agents, who pose as normal citizens and report any person with subversive tendencies. Children are encouraged to report suspicious persons to the government, and some denounce their parents. Citizens are controlled, and the smallest sign of rebellion, even something so small as a facial expression, can result in immediate arrest and imprisonment. Thus, citizens, particularly party members, are compelled to obedience.

“The Principles of Newspeak” is an academic essay appended to the novel. It describes the development of Newspeak, the Party’s minimalist artificial language meant to ideologically align thought and action with the principles of Ingsoc by making “all other modes of thought impossible”. (A linguistic theory about how language may direct thought is the SapirWhorf hypothesis.)

Whether or not the Newspeak appendix implies a hopeful end to Nineteen Eighty-Four remains a critical debate, as it is in Standard English and refers to Newspeak, Ingsoc, the Party etc., in the past tense: “Relative to our own, the Newspeak vocabulary was tiny, and new ways of reducing it were constantly being devised” p.422). Some critics (Atwood,[39] Benstead,[40] Milner,[41] Pynchon[42]) claim that for the essay’s author, both Newspeak and the totalitarian government are in the past.

Nineteen Eighty-Four uses themes from life in the Soviet Union and wartime life in Great Britain as sources for many of its motifs. Some time at an unspecified date after the first American publication of the book, producer Sidney Sheldon wrote to Orwell interested in adapting the novel to the Broadway stage. Orwell sold the American stage rights to Sheldon, explaining that his basic goal with Nineteen Eighty-Four was imagining the consequences of Stalinist government ruling British society:

[Nineteen Eighty-Four] was based chiefly on communism, because that is the dominant form of totalitarianism, but I was trying chiefly to imagine what communism would be like if it were firmly rooted in the English speaking countries, and was no longer a mere extension of the Russian Foreign Office.[43]

The statement “2 + 2 = 5”, used to torment Winston Smith during his interrogation, was a communist party slogan from the second five-year plan, which encouraged fulfillment of the five-year plan in four years. The slogan was seen in electric lights on Moscow house-fronts, billboards and elsewhere.[44]

The switch of Oceania’s allegiance from Eastasia to Eurasia and the subsequent rewriting of history (“Oceania was at war with Eastasia: Oceania had always been at war with Eastasia. A large part of the political literature of five years was now completely obsolete”; ch 9) is evocative of the Soviet Union’s changing relations with Nazi Germany. The two nations were open and frequently vehement critics of each other until the signing of the 1939 Treaty of Non-Aggression. Thereafter, and continuing until the Nazi invasion of the Soviet Union in 1941, no criticism of Germany was allowed in the Soviet press, and all references to prior party lines stoppedincluding in the majority of non-Russian communist parties who tended to follow the Russian line. Orwell had criticised the Communist Party of Great Britain for supporting the Treaty in his essays for Betrayal of the Left (1941). “The Hitler-Stalin pact of August 1939 reversed the Soviet Union’s stated foreign policy. It was too much for many of the fellow-travellers like Gollancz [Orwell’s sometime publisher] who had put their faith in a strategy of construction Popular Front governments and the peace bloc between Russia, Britain and France.”[45]

The description of Emmanuel Goldstein, with a “small, goatee beard”, evokes the image of Leon Trotsky. The film of Goldstein during the Two Minutes Hate is described as showing him being transformed into a bleating sheep. This image was used in a propaganda film during the Kino-eye period of Soviet film, which showed Trotsky transforming into a goat.[46] Goldstein’s book is similar to Trotsky’s highly critical analysis of the USSR, The Revolution Betrayed, published in 1936.

The omnipresent images of Big Brother, a man described as having a moustache, bears resemblance to the cult of personality built up around Joseph Stalin.

The news in Oceania emphasised production figures, just as it did in the Soviet Union, where record-setting in factories (by “Heroes of Socialist Labor”) was especially glorified. The best known of these was Alexey Stakhanov, who purportedly set a record for coal mining in 1935.

The tortures of the Ministry of Love evoke the procedures used by the NKVD in their interrogations,[47] including the use of rubber truncheons, being forbidden to put your hands in your pockets, remaining in brightly lit rooms for days, torture through the use of provoked rodents, and the victim being shown a mirror after their physical collapse.

The random bombing of Airstrip One is based on the Buzz bombs and the V-2 rocket, which struck England at random in 19441945.

The Thought Police is based on the NKVD, which arrested people for random “anti-soviet” remarks.[48] The Thought Crime motif is drawn from Kempeitai, the Japanese wartime secret police, who arrested people for “unpatriotic” thoughts.

The confessions of the “Thought Criminals” Rutherford, Aaronson and Jones are based on the show trials of the 1930s, which included fabricated confessions by prominent Bolsheviks Nikolai Bukharin, Grigory Zinoviev and Lev Kamenev to the effect that they were being paid by the Nazi government to undermine the Soviet regime under Leon Trotsky’s direction.

The song “Under the Spreading Chestnut Tree” (“Under the spreading chestnut tree, I sold you, and you sold me”) was based on an old English song called “Go no more a-rushing” (“Under the spreading chestnut tree, Where I knelt upon my knee, We were as happy as could be, ‘Neath the spreading chestnut tree.”). The song was published as early as 1891. The song was a popular camp song in the 1920s, sung with corresponding movements (like touching your chest when you sing “chest”, and touching your head when you sing “nut”). Glenn Miller recorded the song in 1939.[49]

The “Hates” (Two Minutes Hate and Hate Week) were inspired by the constant rallies sponsored by party organs throughout the Stalinist period. These were often short pep-talks given to workers before their shifts began (Two Minutes Hate), but could also last for days, as in the annual celebrations of the anniversary of the October revolution (Hate Week).

Orwell fictionalized “newspeak”, “doublethink”, and “Ministry of Truth” as evinced by both the Soviet press and that of Nazi Germany.[50] In particular, he adapted Soviet ideological discourse constructed to ensure that public statements could not be questioned.[51]

Winston Smith’s job, “revising history” (and the “unperson” motif) are based on the Stalinist habit of airbrushing images of ‘fallen’ people from group photographs and removing references to them in books and newspapers.[53] In one well-known example, the Soviet encyclopaedia had an article about Lavrentiy Beria. When he fell in 1953, and was subsequently executed, institutes that had the encyclopaedia were sent an article about the Bering Strait, with instructions to paste it over the article about Beria.[54]

Big Brother’s “Orders of the Day” were inspired by Stalin’s regular wartime orders, called by the same name. A small collection of the more political of these have been published (together with his wartime speeches) in English as “On the Great Patriotic War of the Soviet Union” By Joseph Stalin.[55][56] Like Big Brother’s Orders of the day, Stalin’s frequently lauded heroic individuals,[57] like Comrade Ogilvy, the fictitious hero Winston Smith invented to ‘rectify’ (fabricate) a Big Brother Order of the day.

The Ingsoc slogan “Our new, happy life”, repeated from telescreens, evokes Stalin’s 1935 statement, which became a CPSU slogan, “Life has become better, Comrades; life has become more cheerful.”[48]

In 1940 Argentine writer Jorge Luis Borges published Tln, Uqbar, Orbis Tertius which described the invention by a “benevolent secret society” of a world that would seek to remake human language and reality along human-invented lines. The story concludes with an appendix describing the success of the project. Borges’ story addresses similar themes of epistemology, language and history to 1984.[58]

During World War II, Orwell believed that British democracy as it existed before 1939 would not survive the war. The question being “Would it end via Fascist coup d’tat from above or via Socialist revolution from below”?[citation needed] Later, he admitted that events proved him wrong: “What really matters is that I fell into the trap of assuming that ‘the war and the revolution are inseparable’.”[59]

Nineteen Eighty-Four (1949) and Animal Farm (1945) share themes of the betrayed revolution, the person’s subordination to the collective, rigorously enforced class distinctions (Inner Party, Outer Party, Proles), the cult of personality, concentration camps, Thought Police, compulsory regimented daily exercise, and youth leagues. Oceania resulted from the US annexation of the British Empire to counter the Asian peril to Australia and New Zealand. It is a naval power whose militarism venerates the sailors of the floating fortresses, from which battle is given to recapturing India, the “Jewel in the Crown” of the British Empire. Much of Oceanic society is based upon the USSR under Joseph StalinBig Brother. The televised Two Minutes Hate is ritual demonisation of the enemies of the State, especially Emmanuel Goldstein (viz Leon Trotsky). Altered photographs and newspaper articles create unpersons deleted from the national historical record, including even founding members of the regime (Jones, Aaronson and Rutherford) in the 1960s purges (viz the Soviet Purges of the 1930s, in which leaders of the Bolshevik Revolution were similarly treated). A similar thing also happened during the French Revolution in which many of the original leaders of the Revolution were later put to death, for example Danton who was put to death by Robespierre, and then later Robespierre himself met the same fate.

In his 1946 essay “Why I Write”, Orwell explains that the serious works he wrote since the Spanish Civil War (193639) were “written, directly or indirectly, against totalitarianism and for democratic socialism”.[3][60] Nineteen Eighty-Four is a cautionary tale about revolution betrayed by totalitarian defenders previously proposed in Homage to Catalonia (1938) and Animal Farm (1945), while Coming Up for Air (1939) celebrates the personal and political freedoms lost in Nineteen Eighty-Four (1949). Biographer Michael Shelden notes Orwell’s Edwardian childhood at Henley-on-Thames as the golden country; being bullied at St Cyprian’s School as his empathy with victims; his life in the Indian Imperial Police in Burma and the techniques of violence and censorship in the BBC as capricious authority.[61]

Other influences include Darkness at Noon (1940) and The Yogi and the Commissar (1945) by Arthur Koestler; The Iron Heel (1908) by Jack London; 1920: Dips into the Near Future[62] by John A. Hobson; Brave New World (1932) by Aldous Huxley; We (1921) by Yevgeny Zamyatin which he reviewed in 1946;[63] and The Managerial Revolution (1940) by James Burnham predicting perpetual war among three totalitarian superstates. Orwell told Jacintha Buddicom that he would write a novel stylistically like A Modern Utopia (1905) by H. G. Wells.[citation needed]

Extrapolating from World War II, the novel’s pastiche parallels the politics and rhetoric at war’s endthe changed alliances at the “Cold War’s” (194591) beginning; the Ministry of Truth derives from the BBC’s overseas service, controlled by the Ministry of Information; Room 101 derives from a conference room at BBC Broadcasting House;[64] the Senate House of the University of London, containing the Ministry of Information is the architectural inspiration for the Minitrue; the post-war decrepitude derives from the socio-political life of the UK and the US, i.e., the impoverished Britain of 1948 losing its Empire despite newspaper-reported imperial triumph; and war ally but peace-time foe, Soviet Russia became Eurasia.

The term “English Socialism” has precedents in his wartime writings; in the essay “The Lion and the Unicorn: Socialism and the English Genius” (1941), he said that “the war and the revolution are inseparable…the fact that we are at war has turned Socialism from a textbook word into a realisable policy” because Britain’s superannuated social class system hindered the war effort and only a socialist economy would defeat Adolf Hitler. Given the middle class’s grasping this, they too would abide socialist revolution and that only reactionary Britons would oppose it, thus limiting the force revolutionaries would need to take power. An English Socialism would come about which “will never lose touch with the tradition of compromise and the belief in a law that is above the State. It will shoot traitors, but it will give them a solemn trial beforehand and occasionally it will acquit them. It will crush any open revolt promptly and cruelly, but it will interfere very little with the spoken and written word.”[65]

In the world of Nineteen Eighty-Four, “English Socialism”(or “Ingsoc” in Newspeak) is a totalitarian ideology unlike the English revolution he foresaw. Comparison of the wartime essay “The Lion and the Unicorn” with Nineteen Eighty-Four shows that he perceived a Big Brother regime as a perversion of his cherished socialist ideals and English Socialism. Thus Oceania is a corruption of the British Empire he believed would evolve “into a federation of Socialist states, like a looser and freer version of the Union of Soviet Republics”.[66][verification needed]

When first published, Nineteen Eighty-Four was generally well received by reviewers. V. S. Pritchett, reviewing the novel for the New Statesman stated: “I do not think I have ever read a novel more frightening and depressing; and yet, such are the originality, the suspense, the speed of writing and withering indignation that it is impossible to put the book down.”[67] P. H. Newby, reviewing Nineteen Eighty-Four for The Listener magazine, described it as “the most arresting political novel written by an Englishman since Rex Warner’s The Aerodrome.”[68] Nineteen Eighty-Four was also praised by Bertrand Russell, E. M. Forster and Harold Nicolson.[68] On the other hand, Edward Shanks, reviewing Nineteen Eighty-Four for The Sunday Times, was dismissive; Shanks claimed Nineteen Eighty-Four “breaks all records for gloomy vaticination”.[68] C. S. Lewis was also critical of the novel, claiming that the relationship of Julia and Winston, and especially the Party’s view on sex, lacked credibility, and that the setting was “odious rather than tragic”.[69]

Nineteen Eighty-Four has been adapted for the cinema, radio, television and theatre at least twice each, as well as for other art media, such as ballet and opera.

The effect of Nineteen Eighty-Four on the English language is extensive; the concepts of Big Brother, Room 101, the Thought Police, thoughtcrime, unperson, memory hole (oblivion), doublethink (simultaneously holding and believing contradictory beliefs) and Newspeak (ideological language) have become common phrases for denoting totalitarian authority. Doublespeak and groupthink are both deliberate elaborations of doublethink, and the adjective “Orwellian” means similar to Orwell’s writings, especially Nineteen Eighty-Four. The practice of ending words with “-speak” (such as mediaspeak) is drawn from the novel.[70] Orwell is perpetually associated with 1984; in July 1984, an asteroid was discovered by Antonn Mrkos and named after Orwell.

References to the themes, concepts and plot of Nineteen Eighty-Four have appeared frequently in other works, especially in popular music and video entertainment. An example is the worldwide hit reality television show Big Brother, in which a group of people live together in a large house, isolated from the outside world but continuously watched by television cameras.

The book touches on the invasion of privacy and ubiquitous surveillance. From mid-2013 it was publicized that the NSA has been secretly monitoring and storing global internet traffic, including the bulk data collection of email and phone call data. Sales of Nineteen Eighty-Four increased by up to seven times within the first week of the 2013 mass surveillance leaks.[79][80][81] The book again topped the Amazon.com sales charts in 2017 after a controversy involving Kellyanne Conway using the phrase “alternative facts” to explain discrepancies with the media.[82][83][84][85]

The book also shows mass media as a catalyst for the intensification of destructive emotions and violence. Since the 20th century, news and other forms of media have been publicizing violence more often.[86][87] In 2013, the Almeida Theatre and Headlong staged a successful new adaptation (by Robert Icke and Duncan Macmillan), which twice toured the UK and played an extended run in London’s West End. The play opened on Broadway in 2017.

In the decades since the publication of Nineteen Eighty-Four, there have been numerous comparisons to Aldous Huxley’s novel Brave New World, which had been published 17 years earlier, in 1932.[88][89][90][91] They are both predictions of societies dominated by a central government and are both based on extensions of the trends of their times. However, members of the ruling class of Nineteen Eighty-Four use brutal force, torture and mind control to keep individuals in line, but rulers in Brave New World keep the citizens in line by addictive drugs and pleasurable distractions.

In October 1949, after reading Nineteen Eighty-Four, Huxley sent a letter to Orwell and wrote that it would be more efficient for rulers to stay in power by the softer touch by allowing citizens to self-seek pleasure to control them rather than brute force and to allow a false sense of freedom:

Within the next generation I believe that the world’s rulers will discover that infant conditioning and narco-hypnosis are more efficient, as instruments of government, than clubs and prisons, and that the lust for power can be just as completely satisfied by suggesting people into loving their servitude as by flogging and kicking them into obedience.[92]

Elements of both novels can be seen in modern-day societies, with Huxley’s vision being more dominant in the West and Orwell’s vision more prevalent with dictators in ex-communist countries, as is pointed out in essays that compare the two novels, including Huxley’s own Brave New World Revisited.[93][94][95][85]

Comparisons with other dystopian novels like The Handmaid’s Tale, Virtual Light, The Private Eye and Children of Men have also been drawn.[96][97]

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Nineteen Eighty-Four – Wikipedia

Ripple Price Prediction: Debate Over XRP Designation Heats Up

Ripple News Update
Although XRP prices are flashing red this morning, Ripple is actually net positive for the weekend. From its Friday lows to the time of this writing, the XRP to USD exchange rate advanced 5.55%.

But that’s not the biggest story in today’s Ripple news update.

No, once again, investors are at odds about XRP. Is it a cryptocurrency? Is it centralized? The questions that have haunted XRP prices for years are back, spread across message boards and forums that support more libertarian digital assets.

These debates may seem crazy to.

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Ethereum Price Forecast: G20 Regulations Would at Least Bring Certainty

Ethereum News Update
Investors tend to panic when international organizations talk about cryptocurrency regulation, but is that really the nightmare scenario?

What we have at the moment seems worse.

With each country or state striking its own path on crypto regulation, investors are left without a clear sense of direction. “Where is the industry headed?” they keep wondering. All the while, a technology that was supposed to transcend borders becomes limited by them.

Just look at the difference around the world.

In the U.S., you have the head of the Securities and Exchange Commission (SEC) saying that blockchains have “incredible promise,” whereas in China and.

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Ripple Price Forecast: Has the Much-Awaited XRP Rally Started?

XRP Prices: Patience Is Warranted
2017 was a great year for investors, where the market environment was characterized by a constant barrage of new all-time highs, low volatility, and a number of high-flying sectors taking center stage. 2018 is turning out to be a whole different beast; a market correction has currently gripped the markets and all the high-flying sectors that led the market late last year are currently correcting.

Cryptocurrencies were by far the best-performing asset class last year, and it shouldn’t be too shocking that they are the worst-performing asset class this year. For example, Ripple staged an epic advance in 2017, tacking on an incredible 3,216.67%.

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Litecoin Price Forecast: “Tokyo Whale” Continues to Drive Crypto Sell-Off

Litecoin News Update
Remember when hackers broke into the Mt. Gox exchange? That security breach—which took place several years ago and resulted in the loss of billions in Bitcoin—continues to roil cryptocurrency markets to this day.

In order to understand the story, you have to know the history.

So let’s start with what happened after Mt. Gox was hacked. To begin with, investors were compensated for their loss in fiat currency. Yen instead of Bitcoin, as it were. But then some of the missing Bitcoin were recovered. Over time,.

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Ripple Price Forecast: XRP vs SWIFT, SEC Updates, and More

Ripple vs SWIFT: The War Begins
While most criticisms of XRP do nothing to curb my bullish Ripple price forecast, there is one obstacle that nags at my conscience. Its name is SWIFT.

The Society for Worldwide Interbank Financial Telecommunication (SWIFT) is the king of international payments.

It coordinates wire transfers across 11,000 banks in more than 200 countries and territories, meaning that in order for XRP prices to ascend to $10.00, Ripple needs to launch a successful coup. That is, and always has been, an unwritten part of Ripple’s story.

We’ve seen a lot of progress on that score. In the last three years, Ripple wooed more than 100 financial firms onto its.

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Cryptocurrency Price Forecast: Trust Is Growing, But Prices Are Falling

Trust Is Growing…
Before we get to this week’s cryptocurrency news, analysis, and our cryptocurrency price forecast, I want to share an experience from this past week. I was at home watching the NBA playoffs, trying to ignore the commercials, when a strange advertisement caught my eye.

It followed a tomato from its birth on the vine to its end on the dinner table (where it was served as a bolognese sauce), and a diamond from its dusty beginnings to when it sparkled atop an engagement ring.

The voiceover said: “This is a shipment passed 200 times, transparently tracked from port to port. This is the IBM blockchain.”

Let that sink in—IBM.

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The Epic Relation Between Bitcoin and the Stock Market

Bitcoin Prices Are Less Independent Than You Think
Inside the world of cryptocurrencies, some truths go unquestioned: 1) centralization is terrible, 2) fixed money supplies are great, 3) cryptocurrencies are uncorrelated from stocks.

The last “truth” is now in question.

Many analysts, myself included, have raised questions about Bitcoin following the stock market before, but none of us made the case as strongly as Forbes contributor Clem Chambers.

Chambers recently used intraday trade charts to show that Bitcoin prices often follow the same patterns as the Dow Jones Index. (Source: “.

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Ethereum Price Forecast: Big Corporate Moves Could Bolster ETH Prices

Crypto Rally Slows Down
As I write this report, cryptocurrency prices are in the middle of a vicious tug of war between the bulls and the bears. And the bears are winning right now.

Most, if not all, of our favorite cryptocurrencies trended down over the last seven days, erasing the progress they made in earlier weeks.

Short-term volatility is completely overtaking the market, making it tough for existing holders of crypto assets.

But…

If you’re someone who is looking to enter the market, a sell-off is exactly the right time. How many times have I heard investors say, “If I had bought Bitcoin two years ago, I would have made [insert insane profits.

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Ethereum Price Forecast: Big Corporate Moves Could Bolster ETH Prices

Cryptocurrency Price Forecast: What You Need to Know This Week

Cryptocurrency Rally Holds Strong
Rallies are important, but holding a rally is even more important.

Thankfully, that’s what cryptocurrencies have done over the last two weeks. Our favorites either stuck close to their previous levels or they exploded to the upside.

Siacoin (SC), for example, rose more than 24% in a single trading session, leading to a cumulative gain of 108% since we first recommended it last month.

Not bad, right? There aren’t too many investments that can boast of triple-digit gains in one month.

Speaking of triple-digit winners, Ethereum (ETH) rose above 100% for the first time in six weeks. It almost erased its gains in early April, but the.

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Ripple Price Prediction: xRapid Shows Success, But SEC Still Holds Power

XRP Prices Hang in the Balance
Ripple bears like to claim that XRP “serves no purpose” in its technology, but recent success with the “xRapid” software says otherwise. That—plus the continual “Is XRP a security?” debate—drove Ripple prices round and round in circles last week.

I see these two forces working in opposite directions.

Investors should be happy that xRapid is providing genuine benefits to businesses that dared to take a chance on XRP. But does it matter if the U.S. Securities & Exchange Commission (SEC) designates XRP a security?
xRapid Success
For the uninitiated, Ripple has multiple offerings. One is “xCurrent,” a.

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Ripple Price Prediction: xRapid Shows Success, But SEC Still Holds Power

Gene Therapy and Children – KidsHealth

Gene therapy carries the promise of cures for many diseases and for types of medical treatment that didn’t seem possible until recently. With its potential to eliminate and prevent hereditary diseases such as cystic fibrosis and hemophilia and its use as a possible cure for heart disease, AIDS, and cancer, gene therapy is a potential medical miracle-worker.

But what about gene therapy for children? There’s a fair amount of risk involved, so thus far only seriously ill kids or those with illnesses that can’t be cured by standard medical treatments have been involved in clinical trials using gene therapy.

As those studies continue, gene therapy may soon offer hope for children with serious illnesses that don’t respond to conventional therapies.

Our genes help make us unique. Inherited from our parents, they go far in determining our physical traits like eye color and the color and texture of our hair. They also determine things like whether babies will be male or female, the amount of oxygen blood can carry, and the likelihood of getting certain diseases.

Genes are composed of strands of a molecule called DNA and are located in single file within the chromosomes. The genetic message is encoded by the building blocks of the DNA, which are called nucleotides. Approximately 3 billion pairs of nucleotides are in the chromosomes of a human cell, and each person’s genetic makeup has a unique sequence of nucleotides. This is mainly what makes us different from one another.

Scientists believe that every human has about 25,000 genes per cell. A mutation, or change, in any one of these genes can result in a disease, physical disability, or shortened life span. These mutations can be passed from one generation to another, inherited just like a mother’s curly hair or a father’s brown eyes. Mutations also can occur spontaneously in some cases, without having been passed on by a parent. With gene therapy, the treatment or elimination of inherited diseases or physical conditions due to these mutations could become a reality.

Gene therapy involves the manipulation of genes to fight or prevent diseases. Put simply, it introduces a “good” gene into a person who has a disease caused by a “bad” gene.

The two forms of gene therapy are:

Currently, gene therapy is done only through clinical trials, which often take years to complete. After new drugs or procedures are tested in laboratories, clinical trials are conducted with human patients under strictly controlled circumstances. Such trials usually last 2 to 4 years and go through several phases of research. In the United States, the U.S. Food and Drug Administration (FDA) must then approve the new therapy for the marketplace, which can take another 2 years.

The most active research being done in gene therapy for kids has been for genetic disorders (like cystic fibrosis). Other gene therapy trials involve children with severe immunodeficiencies, such as adenosine deaminase (ADA) deficiency (a rare genetic disease that makes kids prone to serious infection), sickle cell anemia, thalassemia, hemophilia, and those with familial hypercholesterolemia (extremely high levels of serum cholesterol).

Gene therapy does have risks and limitations. The viruses and other agents used to deliver the “good” genes can affect more than the cells for which they’re intended. If a gene is added to DNA, it could be put in the wrong place, which could potentially cause cancer or other damage.

Genes also can be “overexpressed,” meaning they can drive the production of so much of a protein that they can be harmful. Another risk is that a virus introduced into one person could be transmitted to others or into the environment.

Gene therapy trials in children present an ethical dilemma, according to some gene therapy experts. Kids with an altered gene may have mild or severe effects and the severity often can’t be determined in infants. So just because some kids appear to have a genetic problem doesn’t mean they’ll be substantially affected by it, but they’ll have to live with the knowledge of that problem.

Kids could be tested for disorders if there is a medical treatment or a lifestyle change that could be beneficial or if knowing they don’t carry the gene reduces the medical surveillance needed. For example, finding out a child doesn’t carry the gene for a disorder that runs in the family might mean that he or she doesn’t have to undergo yearly screenings or other regular exams.

To cure genetic diseases, scientists must first determine which gene or set of genes causes each disease. The Human Genome Project and other international efforts have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in the human cell. This research will provide new strategies to diagnose, treat, cure, and possibly prevent human diseases.

Although this information will help scientists determine the genetic basis of many diseases, it will be a long time before diseases actually can be treated through gene therapy.

Gene therapy’s potential to revolutionize medicine in the future is exciting, and hopes are high for its role in ;curing and preventing childhood diseases. One day it may be possible to treat an unborn child for a genetic disease even before symptoms appear.

Scientists hope that the human genome mapping will help lead to cures for many diseases and that successful clinical trials will create new opportunities. For now, however, it’s a wait-and-see situation, calling for cautious optimism./p>

Date reviewed: April 2014

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Gene Therapy and Children – KidsHealth

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which, unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147] CRISPR gene editing technology has also been used on mice to treat deafness due to the DFNA36 mutation, which also affects humans.[148]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[149] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[150]

Athletes might adopt gene therapy technologies to improve their performance.[151] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[152]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[153][154][155] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[156][157] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[158]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[159]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[160] and such concerns have continued as technology progressed.[161][162] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[149][163] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[164][165] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[166]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[167]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[168]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[169] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[170] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[169]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[171][172]

Gene therapy is the basis for the plotline of the film I Am Legend[173] and the TV show Will Gene Therapy Change the Human Race?.[174] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[175]

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Gene therapy – Wikipedia

Gene Therapy :: Sangamo Therapeutics, Inc. (SGMO)

Sangamo is developing state of the art AAV-based gene therapies for the treatment of monogenic diseases, such as hemophilia A and certain inherited metabolic disorders.

A gene is a unit of genetic information contained in an organisms genome or DNA, which encodes the instructions for making a protein. Collectively, genes provide the information for the organisms development and characteristics. Humans have about 20,000 genes on their 23 pairs of chromosomes.

In monogenic diseases an essential protein isnt made properly, or in sufficient quantities, as a result of a mutation in a single gene. One therapeutic solution is to deliver a new copy of the defective gene to cells so that they can now make the protein and alleviate symptoms of the disease. This is known as gene therapy.

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Gene Therapy :: Sangamo Therapeutics, Inc. (SGMO)

Gene Therapy and Children – KidsHealth

Gene therapy carries the promise of cures for many diseases and for types of medical treatment that didn’t seem possible until recently. With its potential to eliminate and prevent hereditary diseases such as cystic fibrosis and hemophilia and its use as a possible cure for heart disease, AIDS, and cancer, gene therapy is a potential medical miracle-worker.

But what about gene therapy for children? There’s a fair amount of risk involved, so thus far only seriously ill kids or those with illnesses that can’t be cured by standard medical treatments have been involved in clinical trials using gene therapy.

As those studies continue, gene therapy may soon offer hope for children with serious illnesses that don’t respond to conventional therapies.

Our genes help make us unique. Inherited from our parents, they go far in determining our physical traits like eye color and the color and texture of our hair. They also determine things like whether babies will be male or female, the amount of oxygen blood can carry, and the likelihood of getting certain diseases.

Genes are composed of strands of a molecule called DNA and are located in single file within the chromosomes. The genetic message is encoded by the building blocks of the DNA, which are called nucleotides. Approximately 3 billion pairs of nucleotides are in the chromosomes of a human cell, and each person’s genetic makeup has a unique sequence of nucleotides. This is mainly what makes us different from one another.

Scientists believe that every human has about 25,000 genes per cell. A mutation, or change, in any one of these genes can result in a disease, physical disability, or shortened life span. These mutations can be passed from one generation to another, inherited just like a mother’s curly hair or a father’s brown eyes. Mutations also can occur spontaneously in some cases, without having been passed on by a parent. With gene therapy, the treatment or elimination of inherited diseases or physical conditions due to these mutations could become a reality.

Gene therapy involves the manipulation of genes to fight or prevent diseases. Put simply, it introduces a “good” gene into a person who has a disease caused by a “bad” gene.

The two forms of gene therapy are:

Currently, gene therapy is done only through clinical trials, which often take years to complete. After new drugs or procedures are tested in laboratories, clinical trials are conducted with human patients under strictly controlled circumstances. Such trials usually last 2 to 4 years and go through several phases of research. In the United States, the U.S. Food and Drug Administration (FDA) must then approve the new therapy for the marketplace, which can take another 2 years.

The most active research being done in gene therapy for kids has been for genetic disorders (like cystic fibrosis). Other gene therapy trials involve children with severe immunodeficiencies, such as adenosine deaminase (ADA) deficiency (a rare genetic disease that makes kids prone to serious infection), sickle cell anemia, thalassemia, hemophilia, and those with familial hypercholesterolemia (extremely high levels of serum cholesterol).

Gene therapy does have risks and limitations. The viruses and other agents used to deliver the “good” genes can affect more than the cells for which they’re intended. If a gene is added to DNA, it could be put in the wrong place, which could potentially cause cancer or other damage.

Genes also can be “overexpressed,” meaning they can drive the production of so much of a protein that they can be harmful. Another risk is that a virus introduced into one person could be transmitted to others or into the environment.

Gene therapy trials in children present an ethical dilemma, according to some gene therapy experts. Kids with an altered gene may have mild or severe effects and the severity often can’t be determined in infants. So just because some kids appear to have a genetic problem doesn’t mean they’ll be substantially affected by it, but they’ll have to live with the knowledge of that problem.

Kids could be tested for disorders if there is a medical treatment or a lifestyle change that could be beneficial or if knowing they don’t carry the gene reduces the medical surveillance needed. For example, finding out a child doesn’t carry the gene for a disorder that runs in the family might mean that he or she doesn’t have to undergo yearly screenings or other regular exams.

To cure genetic diseases, scientists must first determine which gene or set of genes causes each disease. The Human Genome Project and other international efforts have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in the human cell. This research will provide new strategies to diagnose, treat, cure, and possibly prevent human diseases.

Although this information will help scientists determine the genetic basis of many diseases, it will be a long time before diseases actually can be treated through gene therapy.

Gene therapy’s potential to revolutionize medicine in the future is exciting, and hopes are high for its role in ;curing and preventing childhood diseases. One day it may be possible to treat an unborn child for a genetic disease even before symptoms appear.

Scientists hope that the human genome mapping will help lead to cures for many diseases and that successful clinical trials will create new opportunities. For now, however, it’s a wait-and-see situation, calling for cautious optimism./p>

Date reviewed: April 2014

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Gene Therapy and Children – KidsHealth

Gene therapy – Mayo Clinic

Overview

Gene therapy involves altering the genes inside your body’s cells in an effort to treat or stop disease.

Genes contain your DNA the code that controls much of your body’s form and function, from making you grow taller to regulating your body systems. Genes that don’t work properly can cause disease.

Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body’s ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Researchers are still studying how and when to use gene therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.

Gene therapy is used to correct defective genes in order to cure a disease or help your body better fight disease.

Researchers are investigating several ways to do this, including:

Gene therapy has some potential risks. A gene can’t easily be inserted directly into your cells. Rather, it usually has to be delivered using a carrier, called a vector.

The most common gene therapy vectors are viruses because they can recognize certain cells and carry genetic material into the cells’ genes. Researchers remove the original disease-causing genes from the viruses, replacing them with the genes needed to stop disease.

This technique presents the following risks:

The gene therapy clinical trials underway in the U.S. are closely monitored by the Food and Drug Administration and the National Institutes of Health to ensure that patient safety issues are a top priority during research.

Currently, the only way for you to receive gene therapy is to participate in a clinical trial. Clinical trials are research studies that help doctors determine whether a gene therapy approach is safe for people. They also help doctors understand the effects of gene therapy on the body.

Your specific procedure will depend on the disease you have and the type of gene therapy being used.

For example, in one type of gene therapy:

Viruses aren’t the only vectors that can be used to carry altered genes into your body’s cells. Other vectors being studied in clinical trials include:

The possibilities of gene therapy hold much promise. Clinical trials of gene therapy in people have shown some success in treating certain diseases, such as:

But several significant barriers stand in the way of gene therapy becoming a reliable form of treatment, including:

Gene therapy continues to be a very important and active area of research aimed at developing new, effective treatments for a variety of diseases.

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this disease.

Dec. 29, 2017

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Gene therapy – Mayo Clinic

Gene Therapy | Pfizer: One of the world’s premier …

Gene therapy is a technology aimed at correcting or fixing a gene that may be defective. This exciting and potentially transformative area of research is focused on the development of potential treatments for monogenic diseases, or diseases that are caused by a defect in one gene.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

The technology involves the introduction of genetic material (DNA or RNA) into the body, often through delivering a corrected copy of a gene to a patients cells to compensate for a defective one, using a viral vector.

Viral vectors can be developed using adeno-associated virus (AAV), a naturally occurring virus which has been adapted for gene therapy use. Its ability to deliver genetic material to a wide range of tissues makes AAV vectors useful for transferring therapeutic genes into target cells. Gene therapy research holds tremendous promise in leading to the possible development of highly-specialized, potentially one-time delivery treatments for patients suffering from rare, monogenic diseases.

Pfizer aims to build an industry-leading gene therapy platform with a strategy focused on establishing a transformational portfolio through in-house capabilities, and enhancing those capabilities through strategic collaborations, as well as potential licensing and M&A activities.

We’re working to access the most effective vector designs available to build a robust clinical stage portfolio, and employing a scalable manufacturing approach, proprietary cell lines and sophisticated analytics to support clinical development.

In addition, we’re collaborating with some of the foremost experts in this field, through collaborations with Spark Therapeutics, Inc., on a potentially transformative gene therapy treatment for hemophilia B, which received Breakthrough Therapy designation from the US Food and Drug Administration, and 4D Molecular Therapeutics to discover and develop targeted next-generation AAV vectors for cardiac disease.

Gene therapy holds the promise of bringing true disease modification for patients suffering from devastating diseases, a promise were working to seeing become a reality in the years to come.

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Gene Therapy | Pfizer: One of the world’s premier …

Gene therapy – Wikipedia

In the medicine field, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease.[1][2] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[3] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[4]

Not all medical procedures that introduce alterations to a patient’s genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[5] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it’s unlikely it produced any significant beneficial effects treating beta-thalassemia.

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a “vector”, which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers’ attention, although as of 2014, it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber’s congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson’s disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[26] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[28] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36] As of 2016 these approaches were still years from being medicine.[37][38]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism’s cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host’s cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus’s genetic material with therapeutic DNA. (The term ‘DNA’ may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host’s genome, becoming a permanent part of the host’s DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999. Jesse Gelsinger died because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

In 1972 Friedmann and Roblin authored a paper in Science titled “Gene therapy for human genetic disease?”[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient’s blood cells was replaced by the functional variant. Ashantis immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or “bubble boy” disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial’s Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother’s placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew’s blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

Jesse Gelsinger’s death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial – n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which, unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient’s haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102] As of 2016, only one person had been treated with drug.[103]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission “or very close to it” three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients’ immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as “bubble children.”[18]

Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[18][113]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA “breakthrough” status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys’ cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing “scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans” until the full implications “are discussed among scientific and governmental organizations”.[124][125][126][127]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla’s disease had been regarded as terminal before the treatment.[129]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[135]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or “CAR-T”) that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient’s blood clotting levels.[143][144]

In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber’s congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147] CRISPR gene editing technology has also been used on mice to treat deafness due to the DFNA36 mutation, which also affects humans.[148]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[149] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[150]

Athletes might adopt gene therapy technologies to improve their performance.[151] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[152]

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[153][154][155] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[156][157] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[158]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that “genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics.”[159]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[160] and such concerns have continued as technology progressed.[161][162] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[149][163] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[164][165] once answers have been found to safety and efficiency problems “but only for serious conditions under stringent oversight.”[166]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association’s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[167]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH’s Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[168]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[169] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[170] The protocol for a gene therapy clinical trial must be approved by the NIH’s Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[169]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[171][172]

Gene therapy is the basis for the plotline of the film I Am Legend[173] and the TV show Will Gene Therapy Change the Human Race?.[174] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files’ first season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[175]

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Gene therapy – Wikipedia

Gene Therapy and Children – KidsHealth

Gene therapy carries the promise of cures for many diseases and for types of medical treatment that didn’t seem possible until recently. With its potential to eliminate and prevent hereditary diseases such as cystic fibrosis and hemophilia and its use as a possible cure for heart disease, AIDS, and cancer, gene therapy is a potential medical miracle-worker.

But what about gene therapy for children? There’s a fair amount of risk involved, so thus far only seriously ill kids or those with illnesses that can’t be cured by standard medical treatments have been involved in clinical trials using gene therapy.

As those studies continue, gene therapy may soon offer hope for children with serious illnesses that don’t respond to conventional therapies.

Our genes help make us unique. Inherited from our parents, they go far in determining our physical traits like eye color and the color and texture of our hair. They also determine things like whether babies will be male or female, the amount of oxygen blood can carry, and the likelihood of getting certain diseases.

Genes are composed of strands of a molecule called DNA and are located in single file within the chromosomes. The genetic message is encoded by the building blocks of the DNA, which are called nucleotides. Approximately 3 billion pairs of nucleotides are in the chromosomes of a human cell, and each person’s genetic makeup has a unique sequence of nucleotides. This is mainly what makes us different from one another.

Scientists believe that every human has about 25,000 genes per cell. A mutation, or change, in any one of these genes can result in a disease, physical disability, or shortened life span. These mutations can be passed from one generation to another, inherited just like a mother’s curly hair or a father’s brown eyes. Mutations also can occur spontaneously in some cases, without having been passed on by a parent. With gene therapy, the treatment or elimination of inherited diseases or physical conditions due to these mutations could become a reality.

Gene therapy involves the manipulation of genes to fight or prevent diseases. Put simply, it introduces a “good” gene into a person who has a disease caused by a “bad” gene.

The two forms of gene therapy are:

Currently, gene therapy is done only through clinical trials, which often take years to complete. After new drugs or procedures are tested in laboratories, clinical trials are conducted with human patients under strictly controlled circumstances. Such trials usually last 2 to 4 years and go through several phases of research. In the United States, the U.S. Food and Drug Administration (FDA) must then approve the new therapy for the marketplace, which can take another 2 years.

The most active research being done in gene therapy for kids has been for genetic disorders (like cystic fibrosis). Other gene therapy trials involve children with severe immunodeficiencies, such as adenosine deaminase (ADA) deficiency (a rare genetic disease that makes kids prone to serious infection), sickle cell anemia, thalassemia, hemophilia, and those with familial hypercholesterolemia (extremely high levels of serum cholesterol).

Gene therapy does have risks and limitations. The viruses and other agents used to deliver the “good” genes can affect more than the cells for which they’re intended. If a gene is added to DNA, it could be put in the wrong place, which could potentially cause cancer or other damage.

Genes also can be “overexpressed,” meaning they can drive the production of so much of a protein that they can be harmful. Another risk is that a virus introduced into one person could be transmitted to others or into the environment.

Gene therapy trials in children present an ethical dilemma, according to some gene therapy experts. Kids with an altered gene may have mild or severe effects and the severity often can’t be determined in infants. So just because some kids appear to have a genetic problem doesn’t mean they’ll be substantially affected by it, but they’ll have to live with the knowledge of that problem.

Kids could be tested for disorders if there is a medical treatment or a lifestyle change that could be beneficial or if knowing they don’t carry the gene reduces the medical surveillance needed. For example, finding out a child doesn’t carry the gene for a disorder that runs in the family might mean that he or she doesn’t have to undergo yearly screenings or other regular exams.

To cure genetic diseases, scientists must first determine which gene or set of genes causes each disease. The Human Genome Project and other international efforts have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in the human cell. This research will provide new strategies to diagnose, treat, cure, and possibly prevent human diseases.

Although this information will help scientists determine the genetic basis of many diseases, it will be a long time before diseases actually can be treated through gene therapy.

Gene therapy’s potential to revolutionize medicine in the future is exciting, and hopes are high for its role in ;curing and preventing childhood diseases. One day it may be possible to treat an unborn child for a genetic disease even before symptoms appear.

Scientists hope that the human genome mapping will help lead to cures for many diseases and that successful clinical trials will create new opportunities. For now, however, it’s a wait-and-see situation, calling for cautious optimism./p>

Date reviewed: April 2014

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Gene Therapy and Children – KidsHealth