In 2018, when he was 13, Ethan Ralstons eyesight started to get blurry. The diagnosis was devastating. He had been born with Leber Hereditary Optic Neuropathy (lhon), a rare genetic disorder that eats away at the cells of the optic nerve until it causes blindness.

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Given that America and Europe between them see just 800 cases of lhon a year young Mr Ralston was very unlucky. In another way, though, he could be counted fortunate. GenSight, a French biotech company, had for years been working on a gene therapy for lhon. The condition is caused by a mutation in a gene called nd4 which causes the bodys cells to make a faulty protein. The therapy, called Lumevoq, sought to resolve the problem by adding the canonical version of nd4 to cells in the retina and optic nerve. By 2018 Lumevoq was in clinical trials. Shortly after his diagnosis Mr Ralston was treated with it.

Today his eyesight has almost returned to normal. He can work on a computer, drive a car, go bowling with his friends. He would seem to be cured.

Such stories are becoming increasingly common. In the 2010s a whole year might see only one new gene-therapy approval from regulators. This August alone saw two, one for beta thalassaemia and one for haemophilia a, both diseases of the blood. The Alliance for Regenerative Medicine, an international industry group for cell and gene therapies, says that 1,369 groups are developing such treatments and just over 2,000 clinical trials are under way. Most of those in their earliest stages and may well progress no further: many are cell therapies which do not require changes to the patients genes. Still, according to scientists from the Centre for Biomedical Innovation in Cambridge, Massachusetts, there are enough trials under way that 40-50 new gene therapies could be approved for clinical use by 2030.

A lot of these will be used in the fight against cancer. Removing from the body some of the t-cells which the immune system uses to fight cancer, giving them a gene that lets them recognise a cancer-specific trait and putting them back is the basis of car-t therapies, one of the hottest approaches around (the car stands for chimeric antigen receptor). But there will also be lots that tackle inherited diseases. There are clear signs that this surge has begun. Janet Lambert, the boss of the Alliance for Regenerative Medicine, anticipates that Europe and America will see a record number of such gene therapies approved this year (see table).

In a world where saying that something is in some person or other entitys dna has become a shorthand for seeing it as part of their very essence, dealing with inherited diseases this way looks truly revolutionary. It is one of the most compelling concepts in modern medicine as a recent review paper put it. The ability to provide someone with a single treatment that will alleviate a terrible condition for a decade or moreperhaps even for lifeis an intervention without any obvious parallel.

But it comes with a number of challenges. The techniques being used still carry risks. The therapies themselves are enormously expensive, not just because of the research required to develop themthat is expensive all across the biotech worldbut because the cost of making them is particularly high. What is more, some may face stiff competition from other approaches, some of them equally novel. These may allow some of the conditions gene therapy seeks to fix to be treated in cheaper ways.

This raises the possibility that, impressive as they are, gene therapies might be relegated to a niche treating a small number of patients in rich countries. That would be a poor outlook for millions around the world who suffer from more common genetic diseases, such as sickle-cell disease, and other conditions. It could also scupper the chances of gene therapy moving beyond the realm of single-gene disorders to tackle more complex conditions. For many more people to experience the sort of benefits that have changed Mr Ralstons prospects, the ability to produce miracles will not be enough. They have to be produced affordably in ways that can be adapted to conditions far removed from the elite hospitals where trials typically take place today.

To design a gene therapy, you need a gene you want to add to the patients cells and a way of getting it into them. Finding the first is, in principle, easy: thousands of diseases, most of the worst thankfully rare, come about because of a garbled copy of a single gene. That means they might in principle be alleviated by the addition of the normal version. The second is normally the job of a modified virus that can no longer reproduce but that can get a new gene into its target cells: a viral vector.

Sometimes cells are taken out of the body, transformed by a vector and put back in, as they are in car-t cancer therapies. Zynteglo, a gene therapy for beta thalassaemia made by bluebird bio, a startup with an aversion to capital letters, works this way. On August 17th it became the third gene therapy for an inherited disease to be approved by Americas Food and Drug Administration (fda). In other cases the vector does its work inside the body. Lumevoqauthorised for use in France in 2021, but not yet by the European Medicines Agency (ema) or the fdawas injected directly into Mr Ralstons eyes.

The first gene-therapy trial, which treated a single child with a specific and severe immunodeficiency called ada-scid, got under way in 1990. It did not lead quickly to a commercial product (a different gene therapy for ada-scid, Strimvelis, was eventually approved in 2016) but it paved the way for a number of successors. Unfortunately in 1999 the nascent field was rocked by the death of Jesse Gelsinger, an 18-year-old, four days after he had been given a gene intended to fix his inherited inability to metabolise ammonia.

His death was caused by his immune systems response to the adenovirus used as a vector. That knowledge drove the hunt for safer vectors; James Wilson, a gene-therapy pioneer at the University of Pennsylvania, where the trial during which Mr Gelsinger died was based, uncovered the potential of adeno-associated viruses (aav). These are widespread in humans and are not known to cause any sort of disease; they provoke little or no immune response. Similar advantages are sought by vaccine-makers when they look for vectors. (The Oxford AstraZeneca covid-19 vaccine works in this way, using an adenovirus to put dna describing a telltale viral protein into the bodys cells.)

For gene therapies, aavs have the big advantage of coming in more than 100 different flavours, or serotypes, each of which has different preferences when it comes to which sorts of cell to infect. Vectors derived from aavs are able to home in on specific tissues such as the optic nerve, or the central nervous system, or the muscles.

However, aav-based vectors are not without problems. A recent analysis of almost 150 gene-therapy trials using them found that 35% had seen serious adverse events, including brain-imaging findings of uncertain significance. Large doses of the vector have also been linked to safety concerns. In 2018 Dr Wilson warned that high doses of aav caused life-threatening toxicity in piglets and monkeys. At the same time he resigned from the scientific advisory board of Solid Biosciences, a gene-therapy firm focused on muscular dystrophy, citing emerging concerns about the possible risks of too much aav. The firm says his resignation was due to findings in experiments that were unrelated to its work. Nonetheless its regulatory filings acknowledge that the high dosing requirements for the therapy it is developing may increase the risk of side-effects.

In August Novartis, a Swiss drug company, reported two liver-related deaths in children who were treated with its gene therapy for spinal muscular atrophy (sma). Trials of a therapy being developed by Astellas, a Japanese drug company, for a rare muscle disease called x-linked myotubular myopathy produced some spectacular results, but also saw three children die with sepsis and gastrointestinal bleeding as a consequence of liver failure and a fourth from other liver-related complications.

Bernhardt Zeiher, who is about to retire as Astellass head of development, recently told Endpoints, an online publication, that the company thinks the deaths were caused by a combination of a reaction to the aav vector used and an underlying risk of liver disease. The transformational nature of the therapy itself, he added, means that the firm is committed to finding a way forward in the field.

There have also been concerns over the potential for some vectors to trigger cancers in the long term. You are giving [patients] quadrillions of vector particles, says David Lillicrap, a professor at Queens University in Kingston, Ontario, who works on haemophilia. A very, very small percentage are going to get into the host genome [in] susceptible areas. In 2020 a patient who was being treated for ada-scid with Strimvelis, which uses an rna-based retrovirus as a vector, developed leukaemia. Orchard Therapeutics, the company marketing Strimvelis, has said it may be attributable to the way the gene integrated itself into the genome.

Nicole Paulk of the University of California, San Francisco, says that despite some worrying headlines the aav vector is extraordinarily safe. She says it has been or is being used in over 250 clinical trials with tens of thousands of patients, and that, compared with cancer drugs, it has been remarkably well tolerated.

Given that patients can have terrible experiences with cancer drugs that might not seem reassuring. But there are two other factors to bear in mind. One is that the patients in gene-therapy trials are often very unwell to begin with, and may come into them on other quite arduous treatment regimes. Adverse events are to be expected. More importantly, they may have little if anything by way of other options.

Karen Pignet-Aiach is the founder and boss of Lysogene, a French gene-therapy firm which concentrates on errors in the central nervous system. Firms like hers, she says, have to battle to make sure that regulatory agencies stick to the principle that the risks attached to a treatment have to be balanced against the benefits that a therapy for something lethal and untreatable could bring. In 2020 Lysogene had to deal with the difficult death of a child during a trial, putting a temporary halt to its clinical work. Ms Pignet-Aiach says the death may have been caused by medication given outside the trial but that there was no link with the treatment that was actually being investigated. As to the possible benefits, when she says Our patients have nothing [else] available she knows what she is talking about: she lost a daughter to Sanfilippo syndrome, one of the disorders the company is tackling.

Hold-ups when patients die are understandable, but they increase the cost, and risk, of developing these medicines. And there are other hurdles. Because no one yet knows how many years of duty can be expected from gene therapies, long-term studies are needed; regulators will often insist on them continuing after approval. Because the conditions involved are often progressive and untreatable by other means there are real ethical concerns about randomising trials, something often seen as the best way to clear-cut results.

These problems go some way to explaining the remarkable price of the therapies which make it to marketand which, because of those prices, sometimes leave it soon afterwards. When Glybera, a therapy developed by uniQure, a Dutch company, to address an error in the way fat is processed in a particularly rare condition, got the nod from the ema in 2012 it became the first gene therapy to be approved by a stringent regulator. It also became the first medical treatment with a price tag of $1m. The first approval by the fda, in 2017, was for Luxturna, a gene therapy to prevent another form of progressive vision loss. Roche, a big-pharma company, priced it at $425,000. Per eye. In 2019 Zolgensma, Novatiss treatment for sma, went on sale at $2.1m. Last year the mother of a baby being treated with Zolgensma remarked that everyone who touched the drug, or was around it, had to be trained to handle it: it was like carrying gold. Libmeldy, approved by the ema in 2020 to treat a disorder which degrades the nervous system, costs 2.8m ($3.3m) a dose.

Pharmaceutical companies do not discuss the basis of drugs prices. In America the approach is typically taken to be an assessment of what the market will bear, which has led to an environment accustomed to high prices. The problem with gene therapies is that the price being charged seems in some cases well beyond what the market will bear.

Take Glybera, the first-approved therapy. Only a single dose was ever sold. It has been withdrawn from the European market. According to Stat, another online publication, after the ema approved Zynteglo in 2019 bluebird bio offered it in Germany for $1.8m a treatment; Germany offered to pay $950,000 in cases where it worked, $790,000 when it didnt. The firm subsequently withdrew it from the European market; it has done the same with eli-cell, which treats an irreversible nerve disease. The price it has set for Zynteglo in America is $2.8m.

Some companies are getting out of the market altogether, suggesting they see no way forward. Amicus Therapeutics, a biotech firm which had been working on a number of gene therapies at one point, got out of the field completely earlier this year. Within two years of having put the ada-scid therapy Strimvelis on the market in Europe, gsk, a big drug company, offloaded the treatment to Orchard.

If the makers are worried, so are the buyers. Health systems and insurance firms can cope with one or two such therapies at the far end of the price spectrum. Britains nhs, quite capable of ruling out therapies on the basis of cost, has bought both Zolgensma and Libmeldy (it negotiated a significant discount). But as the number of approved treatments grows the economics are looking more challenging.

A study published this February by the Aspen Institute, a think-tank, and the Blue Cross Blue Shield Association, an association of American insurance companies, looked at the expected arrival of 90 gene therapies and cell therapies. By 2031 the annual acquisition cost for 550,000 patients would be $30bn. With the countrys total prescription-drug bill currently at $577bn, that is relatively small; but it is still significant. Virtually all the buyers for health care in America have warned about the cost burden they expect as the numbers of these products grow.

I think everyone agrees that the pricing of gene therapies is a crisis, says Dr Paulk. The crisis has two main drivers: the amount of work needed to develop and make the therapies and the lack of good models for pricing one-off interventions which could obviate the need for lifelong treatment.

The costs of gene therapies are not just down to arduous research and development and long-drawn-out trials. Making the material which gets put into the patient is not for the faint of heart says Jay Bradner, president of the Novartis Institutes for BioMedical Research. Gene therapies are like snowflakes, says Dr Paulk. Every aav program and every lot is completely unique. Bespoke, though, does not mean small scale. She says that for diseases where you need to get the vector into a particularly large number of cells, such as Duchenne muscular dystrophy, It is not uncommon that we need to use at least a 50 litre, if not a 200 litre, bioreactor to make a single dose for a single patient.

Analysts at the Boston Consulting Group recently estimated that the cost of manufacturing gene therapies ranges from $100,000 to $500,000 per dose. A lot of this manufacturing is done by third parties, and the difficulties of the process can be seen in the limited capacity they offer. Biotech firms that want to get into gene therapy can have to wait up to three years for manufacturing capacity to become available, according to insiders.

On the other side of the coin is the difficulty of calculating benefits. If a $2m treatment really does provide decades of life then the cost per year is down in the tens of thousands of dollarshardly out of line with many other modern therapies. This has led some to suggest that payment might be in annual instalments. In the long term that could make the total larger, but it would spread it out. Another possible innovation is to couple such an approach with the option of stopping paying if the therapy stops working.

The question as to whether the therapy is worth the price has to be answered in the context of what if anything the competition can offer. Take sma, which is caused by a faulty version of a gene called smn1. Zolgensma treats this problem by providing cells with an extra copy of smn1 which works. A treatment called Spinraza uses a method that increases the amount of protein made from a very similar but normally much less productive gene, smn2: its active agent is a molecule called an antisense oligonucleotide.

Antisense treatments are being tried against various conditions which look as if they can be alleviated by getting an existing gene expressed more or less. They are not permanent; Spinraza needs to be administered every four months. Moreover, although the cost of manufacture is far lower than for gene therapies, they are still not cheap. Biogen, the biotech company that makes Spinraza, charges up to $125,000 per dose. But such treatments may well be easier to scale up, and thus see their costs reduced.

Haemophilia, for a form of which Roctavian, made by Biomarin, a biotech company, received ema approval on August 24th, is another condition where alternative approaches have made huge strides, according to Dr Lillicrap. One of the newest antibodies used in its treatment needs to be given only every two to four weeks, rather than every few days, as used to be the case. Artificial versions of the clotting factors haemophiliacs cannot make have been engineered so as to last longer in the blood. There are also clever new ways of lowering the expression of proteins which suppress coagulation.

It is not just what the competition can offer now that matters. It is what it might offer in five or ten years time. Spending a lot on a gene therapy today may prove a good investment if it provides many years of reasonably healthy life. But at the same time it is a bet against the real possibility that a cheaper and possibly better treatment is on the way.

The answer to that conundrum is to make sure that gene therapies get better and cheaper, too. Various companies are looking at ways to improve manufacturing. 64x Bio, based in San Francisco, is testing millions of possible cell lines to try and find those that will grow vectors like aav most efficiently. Others are looking at the vectors themselves, trying to make them less arousing to the immune system, better targeted and more likely to actually carry the gene of interest. Current procedures leave a lot of the vectors empty; increasing the proportion that is filled would reduce dose size and costs.

Ideas for making better things to put in the vectors abound. The field started with basic tools; would-be therapists could put a gene into the genome but had little control over where it went and thus how it might be controlled and what collateral damage it might cause. In the past decade, though, great advances have been made in gene editing, a set of techniques which allow the message in an existing gene to be rewritten. As Fyodor Urnov, a professor at the University of California, Berkeley, puts it, gene therapy is like adding a fifth wheel to a car with a flat tyre; gene editing is repairing the flat.

At present, gene editing is a particularly promising route for therapies in which blood-cell-making stem cells are removed, fiddled with and reinserted into the patients bone marrow. Two clinical trials in which this sort of editing is used against sickle-cell disease, which is brought about by mutations in haemoglobin which make red blood cells deformed and defective, are already well under way. One is for a treatment from Vertex Pharmaceuticals, based in Massachusetts and crispr Therapeutics, the other is by bluebird bio.

More than a dozen patients are reported to have been cured, and it is possible that one of the treatments could be ready for approval next year. There are other gene therapies for the condition at earlier stages. There is also, again, competition from other approaches. On August 8th Pfizer, another big drug company, announced its intention to acquire Global Blood Therapies, a biotech company, for $5.4bn. For that it gets Oxbryta, a drug that stops the mutant haemoglobins from sticking together, and some other therapies.

A similar gene-therapy approach is being used to tackle aids by editing into cells traits that make them immune to hiv. But here the price issue, already confounding, becomes all but lethal. Most people with aids, like most people with sickle-cell disease, live in low- and middle-income countries. According to Mike McCune of the Bill & Melinda Gates Foundation, in countries where antiretroviral therapy for aids costs between $70 and $200 a year an all-out cure for the disease, even if it were possible, would need to come in at $2,000 or less.

If this sounds staggeringly unlikely, it is worth considering that there is a partial precedent. The cost of making target-specific monoclonal antibodies was enormous when they were first developed. But between 1998 and 2009 manufacturing improvements brought about a 50-fold reduction in the cost of goods. Matching that would allow gene therapies to move into middle-income countries, if not low-income ones.

As Mr Ralston can testify, gene therapies border on the miraculous. But they remain miracles of science, their creation incredibly time-intensive [and] people-intensive, as Dr Paulk puts it. Now they must become routinely applicable miracles of medicine. That requires extending the range of conditions they address, learning how long they last and expanding the number of patients they help. In many ways that effort will be more demanding than the work to date. It will have to go well beyond the labs currently tinkering, the charities currently raising funds for rare diseases and the companies desperately trying to find a way to sell the remarkable things they have created. But their remarkable work has made it possible for that second miracle-making effort to begin.

Editors note (September 1st 2022): Due to an editing error, the print and earlier online versions of this article wrongly stated that Lumevoq had been approved by the ema and that Oxford AstraZeneca vaccine used an AAV vector rather than an adenovirus. Sorry.

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Gene therapies must become miracles of medicine | The Economist

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.

Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 61013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.

Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.

Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

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Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A

Cell and gene therapies seek to correct the root cause of an illness at the molecular level. These game-changing medicines are reshaping how we address previously untreatable illnesses transforming peoples lives.

Cell and gene therapy represent overlapping fields of research with similar therapeutic goals developing a treatment that can correct the underlying cause of a disease, often a rare inherited condition that can be life-threatening or debilitating and has limited treatment options.

While these technologies were initially developed in the context of treating rare diseases caused by a single faulty gene, they have since evolved towards tackling more common diseases, says Professor Rafael J. Yez-Muoz, director of the Centre of Gene and Cell Therapy (CGCT) at Royal Holloway University of London.

A powerful example is the chimeric antigen receptor (CAR) T-cell therapies, which have been approved for treating certain blood cancers. The approach involves genetically modifying a patients T cells in the laboratory before reintroducing them into the body to fight their disease.

For the first time, we had an example of gene therapy to treat a more common disease demonstrating that the technology has wide applicability, enthuses Yez-Muoz.

To date, 24 cellular and gene therapy products have received approval from the US Food and Drug Administration (FDA) including life-changing treatments for patients with rare diseases, such as inherited forms of blindness and neuromuscular conditions. A variety of gene and cell-based therapies for both rare and common diseases are also currently in development across many therapeutic areas, offering hope for many more families in coming years.

This webinar will provide an introduction to the regulatory framework for cell and gene therapies and highlight the importance of chemistry, manufacturing and controls. Watch to learn about regulatory concerns, safety and quality testing throughout the product lifecycle and key acronyms and terminology.

Gene therapies seek to introduce specific DNA sequences into a patients body to treat, prevent or potentially cure a disease. This may involve the delivery of a functional gene into cells to replace a gene that is missing or causing a problem or other strategies using nucleic acid sequences (such as antisense oligonucleotides or short interfering RNAs [siRNAs]) to reduce, restore or modify gene expression. More recently, scientists are also developing genome-editing technologies that aim to change the cells DNA at precise locations to treat a specific disease.

The key step in successful gene therapy relies on the safe and efficient delivery of genetic material into the target cells, which is carried out by packaging it into a suitable delivery vehicle (or vector). Many current gene therapies employ modified viruses based on adenoviruses, adeno-associated viruses (AAV), and lentiviruses as vectors due to their intrinsic ability to enter cells. But non-viral delivery systems such as lipid nanoparticles (LNPs) have also been successfully employed to deliver RNA-based therapeutics into cells.

A big advantage of using viral vectors for gene delivery is they are longer lasting than non-viral systems, states Dr. Rajvinder Karda, lecturer in gene therapy at University College London. Many of the rare diseases were aiming to tackle are severe and we need to achieve long-term gene expression for these treatments to be effective.

While improved technological prowess empowers the development of CRISPR-edited therapies, supply-chain and manufacturing hurdles still pose significant barriers to clinical and commercialization timelines. Watch this webinar to learn more about the state of CRISPR cell and gene therapies, challenges in CRISPR therapy manufacturing and a next-generation manufacturing facility.

Viral-vector gene therapies are either administered directly into the patients body (in vivo), or cells harvested from a patient are instead modified in the laboratory (ex vivo) and then reintroduced back into the body. Major challenges for in vivo gene delivery approaches are with the safe and efficient targeting of the therapeutic to the target cells and overcoming any potential immune responses to the vectors.

As well as getting the genetic material into the affected cells, we also need to try and limit it reaching other cells as expressing a gene in a cell where its not normally active could cause problems, explains Dr. Gerry McLachlan, group leader at the Roslin Institute in Edinburgh.

For example, the liver was identified as a major site of toxicity for an AAV-based gene therapy approved for treating spinal muscular atrophy (SMA), a type of motor neuron disease that affects people from a very young age.

Unfortunately, these viruses are leaky as theyre also going to organs that dont need therapy meaning you can get these off-target effects, says Karda. Theres still work to be done to develop and refine these technologies to make them more cell- and organ-specific.

It is also important to ensure the gene is expressed at the right level in the affected cells too high and it may cause side effects and too little may render the treatment ineffective. In a recent major advancement in the field, scientists developed a dimmer switch system Xon that enables gene expression to be precisely controlled through exposure to an orally delivered small molecule drug. This novel system offers an unprecedented opportunity to refine and tailor the application of gene therapies in humans.

Download this whitepaper to discover an electroporation system that resulted in CAR transfection efficiencies as high as 70% in primary human T cells, can avoid the potential risks associated with viral transduction and is able to produce CAR T cells at a sufficient scale for clinical and therapeutic applications.

In 1989, a team of researchers identified the gene that causes the chronic, life-limiting inherited disease cystic fibrosis (CF) the cystic fibrosis transmembrane conductance regulator (CFTR). This was the first ever disease-causing gene to be discovered marking a major milestone in the field of human genetics. In people with CF, mutations in the CFTR gene can result in no CTFR protein, or the protein being made incorrectly or at insufficient levels all of which lead to a cascade of problems that affect the lungs and other organs.

Our team focuses on developing gene therapies to treat respiratory diseases in particular, were aiming to deliver the CTFR gene into lung cells to treat CF patients, says McLachlan.

The results of the UK Respiratory Gene Therapy Consortiums most recent clinical trial showed that an inhaled non-viral CTFR gene therapy formulation led to improvements in patient lung function.

While this was encouraging, the effects were modest and we need to develop a more potent delivery vehicle, explains McLachlan. Weve also been working on a viral-based gene therapy using a lentiviral vector to introduce a healthy copy of the CTFR gene into cells of the lung.

Kardas team focuses on developing novel gene therapy and gene-editing treatments for incurable genetic diseases affecting the central and peripheral nervous system and Yez-Muoz is aiming to develop new treatments for rare neurodegenerative diseases that affect children, including SMA and ataxia telangiectasia (AT).

But a significant barrier for academic researchers around the world is accessing the dedicated resources, facilities and expertise required to scale up and work towards the clinical development and eventually the commercial production of gene and cell therapies. These challenges will need to be addressed and overcome if these important advancements are to successfully deliver their potentially life-changing benefits to patients.

Download this app note to discover how electron activated dissociation can obtain in-depth structural characterization of singly charged, ionizable lipids and related impurities, decrease risk of missing critical low abundance impurities and increase confidence in product quality assessment.

After many decades of effort, the future of gene and cell therapies is incredibly promising. A flurry of recent successes has led to the approval of several life-changing treatments for patients and many more products are in development.

Its no longer just about hope, but now its a reality with a growing number of rare diseases that can be effectively treated with these therapies, describes Yez-Muoz. We now need to think about how we can scale up these technologies to address the thousands of rare diseases that exist and even within these diseases, people will have different mutations, which will complicate matters even further.

But as more of these gene and cell-based therapies are approved, there is a growing urgency to address the challenge of equitable access to these innovative treatments around the world.

Gene therapies have the dubious honor of being the most expensive treatments ever and this isnt sustainable in the longer term, says Yez-Muoz. Just imagine being a parent and knowing there is an effective therapy but your child cant access it that would be absolutely devastating.

See more here:
Cell and Gene Therapy: Rewriting the Future of Medicine - Technology Networks

Biopharma focuses on streamlining biomanufacturing and supply chain issues to drive uptake of cell and gene therapies.

Cell and gene therapies (CGTs) offer significant advances in patient care by helping to treat or potentially cure a range of conditions that have been untouched by small molecule and biologic agents. Over the past two decades, more than 20 CGTs have been approved by FDA in the United States and many of these one-time treatments cost between US$375,00 and US$2 million a shot (1). Given the high financial outlay and patient expectations of these life-saving therapies, it is essential that manufacturers provide integrated services across the whole of the supply chain to ensure efficient biomanufacturing processes and seamless logistics to reduce barriers to uptake.

The following looks at the who, what, when, and why of biomanufacturing and logistics in CGTs in the bio/pharmaceutical industry in more detail.

According to market research, the global gene therapy market will reach US$9.0 billion by 2027 due to favorable reimbursement policies and guidelines, product approvals and fast-track designations, growing demand for chimeric antigen receptor (CAR) T cell-based gene therapies, and improvements in RNA, DNA, and oncolytic viral vectors (1).

In 2020, CGT manufacturers attracted approximately US$2.3 billion in investment funding (1). Key players in the CGT market include Amgen, Bristol-Myers Squibb Company, Dendreon, Gilead Sciences, Novartis, Organogenesis, Roche (Spark Therapeutics), Smith Nephew, and Vericel. In recent years, growth in the CGT market has fueled some high-profile mergers and acquisitions including bluebird bio/BioMarin, Celgene/Juno Therapeutics, Gilead Sciences/Kite, Novartis/AveXis and the CDMO CELLforCURE, Roche/Spark Therapeutics, and Smith & Nephew/Osiris Therapeutics.

Many bio/pharma companies are re-considering their commercialization strategies and have re-invested in R&D to standardize vector productions and purification, implement forward engineering techniques in cell therapies, and improve cryopreservation of cellular samples as well as exploring the development of off-the-shelf allogeneic cell solutions (2).

The successful development of CGTs has highlighted major bottlenecks in the manufacturing facilities, and at times, a shortage of raw materials (3). Pharma companies are now taking a close look at their internal capabilities and either investing in their own manufacturing facilities or outsourcing to contract development and manufacturing organizations (CDMOs) or contract manufacturing organizations (CMOs) to expand their manufacturing abilities (4). Recently, several CDMOsSamsung Biologics, Fujifilm Diosynth, Boehringer Ingelheim, and Lonzahave all expanded their biomanufacturing facilities to meet demand (5).

A major challenge for CGT manufacturers is the seamless delivery of advanced therapies. There is no room for error. If manufacturers cannot deliver the CGT therapy to the patient with ease, the efficacy of the product becomes obsolete. Many of these therapies are not off-the-shelf solutions and therefore require timely delivery and must be maintained at precise temperatures to remain viable. Thus, manufacturers must not only conform to regulations, but they must also put in place logistical processes and contingency plans to optimize tracking, packaging, cold storage, and transportation through the products journey. Time is of the essence, and several manufacturers have failed to meet patient demands, which have significant impacts on the applicability of these agents.

Several CAR T-cell therapies have now been approved; however, research indicates that a fifth of cancer patients who are eligible for CAR-T therapies pass away while waiting for a manufacturing slot (6). Initially, the manufacture of many of these autologous products took around a month, but certain agents can now be produced in fewer than two weeks (7). Companies are exploring new ways to reduce vein-to-vein time (collection and reinfusion) through the development of more advanced gene-transfer tools with CARs (such as transposon, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) among others, and the use of centralized organization with standardized apheresis centers (5). Others are exploring the use of the of allogeneic stem cells including Regen Biopharma, Escape Therapeutics, Lonza, Pluristem Therapeutics, and ViaCord (7).

Several gene therapies have also been approved, mainly in the treatment of rare disease (8). Many companies are evaluating novel gene therapy vectors to increase levels of gene expression/protein productions, reduce immunogenicity and improve durability including Astellas Gene Therapies, Bayer, ArrowHead Pharmaceuticals, Bayer, Bluebird Bio, Intellia Therapeutics, Kystal Biotech, MeiraGTx, Regenxbio, Roche, Rocket Pharmaceuticals, Sangamo Therapeutics, Vertex Pharmaceuticals, Verve Therapeutics, and Voyager Therapeutics (8).

While many biopharma companies have established their own in-house CGT good manufacturing practice (GMP) operation capabilities, others are looking to decentralize manufacturing and improve distribution by relying on external contracts with CDMOs and CMOs such as CELLforCURE, CCRM, Cell Therapies Pty Ltd (CTPL), Cellular Therapeutics Ltd (CTL), Eufets GmbH, Gravitas Biomanufacturing, Hitachi Chemical Advances Therapeutic Solutions, Lonza, MasTHerCell, MEDINET Co., Takara Bio, and XuXi PharmaTech (6, 9, 10).

The top 50 gene therapy start-up companies have attracted more than $11.6 billion in funds in recent years, with the top 10 companies generating US$5.3 billion in series A to D funding rounds (10). US-based Sana Biotechnology leads the field garnering US$700 million to develop scalable manufacturing for genetically engineered cells and its pipeline program, which include CAR-T cell-based therapies in oncology and CNS (Central Nervous System) disorders (11). In second place, Editas Medicine attracted $656.6 million to develop CRISPR nuclease gene editing technologies to develop gene therapies for rare disorders (12).

Overall, CGTs have attracted the pharma industrys attention as they provide an alternative route to target diseases that are poorly served by pharmaceutical and/or medical interventions, such as rare and orphan diseases. Private investors continue to pour money into this sector because a single shot has the potential to bring long-lasting clinical benefits to patients (13). In addition, regulators have approved several products and put in place fast track designation to speed up patient access to these life-saving medicines. Furthermore, healthcare providers have established reimbursement policies and manufacturers have negotiated value- and outcome-based contracts to reduce barriers to access to these premium priced products

On the downside, the manufacture of CGTs is labor intensive and expensive with manufacturing accounting for approximately 25% of operating expenses, plus there is still significant variation in the amount of product produced. On the medical side, many patients may not be suitable candidates for CGTs or not produce durable response due to pre-exposure to the viral vector, poor gene expression, and/or the development of immunogenicity due to pre-exposure to viral vectors. Those that can receive these therapies may suffer infusion site reactions, and unique adverse events such as cytokine release syndrome and neurological problems both of which can be fatal if not treated promptly (14).

Despite the considerable advances that have been made in the CGT field to date, there is still much work needed to enhance the durability of responses, increase biomanufacturing efficiencies and consistency and to implement a seamless supply chain that can ensure these agents are accessible, cost-effective, and a sustainable option to those in need.

Cleo Bern Hartley is a pharma consultant, former pharma analyst, and research scientist.

BioPharm InternationalVol. 35, No. 10October 2022Pages: 4951

When referring to this article, please cite it as C.B. Hartley, "Growth in Cell and Gene Therapy Market," BioPharm International 35 (10) 4951 (2022).

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Growth in Cell and Gene Therapy Market - BioPharm International

ZUG, Switzerland and BOSTON, Sept. 28, 2022 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced that the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation to CTX130, the Companys wholly-owned allogeneic CAR T cell therapy targeting CD70, for the treatment of Mycosis Fungoides and Szary Syndrome (MF/SS).

The RMAT designation is an important milestone for the CTX130 program that recognizes the transformative potential of our cell therapy in patients with T-cell lymphomas based upon encouraging clinical data to date, said Phuong Khanh (P.K.) Morrow, M.D., FACP, Chief Medical Officer of CRISPR Therapeutics. "We continue to work with a sense of urgency to bring our broad portfolio of allogeneic cell therapies to patients in need.

Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising pipeline products, including genetic therapies. A regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such disease or condition. Similar to Breakthrough Therapy designation, RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the biologics license application (BLA) and other opportunities to expedite development and review.

About CTX130 and COBALT TrialsCTX130, a wholly-owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR T investigational therapy targeting Cluster of Differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX130 is being investigated in two ongoing independent Phase 1 single-arm, multi-center, open-label clinical trials that are designed to assess the safety and efficacy of several dose levels of CTX130 in adult patients. The COBALT-LYM trial is evaluating the safety and efficacy of CTX130 for the treatment of relapsed or refractory T or B cell malignancies. The COBALT-RCC trial is evaluating the safety and efficacy of CTX130 for the treatment of relapsed or refractory renal cell carcinoma. CTX130 has received Orphan Drug and Regenerative Medicine Advanced Therapy designations from the FDA.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Boston, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

CRISPR Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements made by Dr. Morrow in this press release, as well as regarding CRISPR Therapeutics expectations about any or all of the following: (i) the status of clinical trials and discussions with regulatory authorities related to product candidates under development by CRISPR Therapeutics including, without limitation, expectations regarding the benefits of RMAT designation; and (ii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients not to be indicative of final trial results; the potential that clinical trial results may not be favorable; potential impacts due to the coronavirus pandemic, such as the timing and progress of clinical trials; that future competitive or other market factors may adversely affect the commercial potential for CRISPR Therapeutics product candidates; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, quarterly report on Form 10-Q and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

CRISPR THERAPEUTICS standard character mark and design logo, CTX130 and COBALT are trademarks and registered trademarks of CRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.

Investor Contact:Susan Kim+1-617-307-7503susan.kim@crisprtx.com

Media Contact:Rachel Eides+1-617-315-4493rachel.eides@crisprtx.com

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CRISPR Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX130 for the Treatment of Cutaneous T-Cell...

Of the 1.5 million people living with lupus in the United States, 90% are women. This disease turns the bodys immune system against itself, potentially causing extreme pain, fatigue, difficulty thinking clearly, and cardiovascular disease.

Officially known as systemic lupus erythematosus, lupus is distinct among autoimmune diseases in the way circulating antibodies proteins that when functioning properly help to protect against disease react against DNA, the bodys instructions for building cells and passing traits from parents to children.

Drs. Peter M. Glazer and James Hansen discovered that one specific lupus antibody, known as 3E10, can penetrate cancer cells and make them sensitive to and killed by standard radiation and chemotherapy methods. Notably, this technique has shown significant effectiveness in killing cancer cells with DNA repair deficiencies, such as those with mutations in the tumor-suppressing BRCA2 gene that lead to higher rates of breast and ovarian cancer.

Now, nearly a decade since this discovery and with he help of a grant from Womens Health Research at Yale, researchers are close to advancing a treatment toward clinical trials while learning more about how this lupus antibody penetrates and kills cancer cells.

This discovery has unlocked promising new pathways for treatment of BRCA-related cancers that affect so many women around the world, said Glazer, the Robert E. Hunter Professor of Therapeutic Radiology, professor of genetics, and chair of the Department of Therapeutic Radiology. We have learned a great deal about how 3E10 interacts with DNA, and we continue to explore how this knowledge could be used to create therapies for other types of difficult-to-treat cancers.

Dr. Glazer and his colleague Dr. James E. Hansen, associate professor of therapeutic radiology, licensed the rights for their antibody discovery to a company, Patrys, Ltd., that has validated the work and developed 3E10 as a cancer therapy for human use. An earlier human study in Switzerland attempting to use 3E10 as a vaccine for lupus had already demonstrated that it is nontoxic. Phase 1 clinical trials could begin as early as next year, Dr. Glazer said, likely for patients with cancers related to mutations of BRCA1/2 genes or of another tumor suppressing gene known as PTEN.

This is very promising, Glazer said. I think it will be important to identify the right subgroup of patients for which this is most effective.

After publishing the results, Dr. Glazer and his colleagues leveraged the data to obtain a pair of large multiyear grants from the National Institutes of Health. With this funding and the help of Yale graduate student Audrey Turchick, the team has discovered that inside a cancer cell, 3E10 sticks to a DNA repair protein called RAD51. This causes the lethality for cancer cells that are deficient in BRCA1 and BRCA2 genes by preventing the cells from conducting the routine DNA repair necessary to sustain themselves.

With ongoing funding from the NIH, Dr. Glazers team, including structural biologist Dr. Franziska Bleichert, is building on these findings to enhance the anti-cancer potency of 3E10 and develop therapeutic strategies by identifying ways for the antibody to stick more strongly to RAD51.

In addition, an MD/PhD student in the lab, Elias Quijano, helped identify the capacity of 3E10 to bind with RNA a type of molecule used to carry out DNA instructions and carry RNA into a cancer cell, potentially with instructions that can kill the cell. Quijano and Drs. Glazer, Stephen Squinto, and Bruce Turner co-founded Gennao Bio, a company seeking to develop this method of cancer-fighting therapy.

This was an unexpected discovery that turns out may be very useful, Glazer said. We have some data showing the efficacy of this method against tumors in a laboratory model. It is a versatile platform, because it can deliver different types of RNA in a similar way to how the COVID-19 mRNA vaccines work.

The research continues, thanks in large part to the investment WHRY made so many years ago.

I think that type of funding is extremely valuable, Glazer said of his WHRY grant. It allowed us to do the sets of exploratory experiments we needed to do to demonstrate our approach was viable and get the larger grants. We showed this is feasible, this is promising.

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Fighting Breast and Ovarian Cancer With a Lupus Antibody - Yale School of Medicine

SAN FRANCISCO, Sept. 29, 2022 (GLOBE NEWSWIRE) -- Excision BioTherapeutics, Inc., a clinical-stage biotechnology company developing CRISPR-based therapies intended to cure viral infectious diseases, todayannounced that the California Institute for Regenerative Medicine (CIRM) has awarded Excision a $6.85 million grant to support the clinical development of the EBT-101 program for human immunodeficiency virus type 1 (HIV-1).

Daniel Dornbusch, Chief Executive Officer of Excision, commented, We are honored that CIRM has recognized the potential value of the EBT-101 program and our dual-guide RNA CRISPR approach to developing curative therapies for HIV-1 as well as other serious viral diseases with significant unmet needs. The CIRM grant provides further validation for the EBT-101 clinical trial, which is the first ever to evaluate an in vivo CRISPR-based therapy in an infectious disease. The grant will provide Excision with important funding to advance the trial and potentially demonstrate the safety and efficacy of removing viral DNA from people affected by the HIV pandemic.

Excision recently reported the first participant in the EBT-101 Phase 1/2 clinical trial was dosed in July 2022, with initial findings indicating the therapeutic has been well tolerated to-date. The participant continues to be monitored for safety and is expected to qualify for analytical treatment interruption (ATI) of their background anti-retroviral therapy (ART) in an evaluation of a potential cure.

To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative, says Maria T. Millan, MD, President and CEO of CIRM. In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.

About EBT-101EBT-101 is a unique, in vivo CRISPR-based therapeutic designed to cure HIV infections after a single intravenous infusion. EBT-101 employs an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and dual guide RNAs, enabling a multiplex editing approach that simultaneously targets three distinct sites within the HIV genome. This allows for the excision of large portions of the HIV genome, thereby minimizing potential viral escape.

About the EBT-101 Clinical ProgramThe EBT-101 Phase 1/2 trial is an open-label, multi-center single ascending dose study designed to evaluate the safety, tolerability and preliminary efficacy of EBT-101 in approximately nine participants with HIV-1 who are suppressed on antiretroviral therapy. The clinical program is supported by preclinical studies that included positive long-term non-human primate safety data and efficacy data in humanized mice showing the potential to cure HIV when treated with EBT-101. The primary objective of the trial is to assess the safety and tolerability of a single dose of EBT-101 in study participants with undetectable viral load on antiretroviral therapy (ART). Biodistribution, pharmacodynamic, and efficacy assessments will also be conducted. All participants will be assessed for eligibility for an analytical treatment interruption (ATI) of their background ART at Week 12 post EBT-101 administration. Following the initial 48-week follow up period, all participants will be enrolled into a long-term follow up protocol. For more information, see ClinicalTrials.gov identifiers NCT05144386 (Phase 1/2 trial) and NCT05143307 (long-term follow up protocol).

About CIRMAt CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission.To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of todays most promising stem cell technologies.With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is one of the worlds largest institutions dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go towww.cirm.ca.gov.

About Excision BioTherapeutics, Inc.Excision BioTherapeutics, Inc. is a clinical-stage biotechnology company developing CRISPR-based therapiesas potentialcures for viral infectious diseases. EBT-101, the Companys lead program, is anin vivoCRISPR-based therapeutic designed to cure HIV infections after a single intravenous infusion. Excisions pipeline unites next-generation CRISPR nucleases with a novel gene editing approach to develop curative therapies for Herpes Virus, JC Virus,which causes PML, and Hepatitis Bvirus. Excisions foundational technologies were developedin the laboratories of Dr. KamelKhaliliat Temple University andDr. JenniferDoudnaatthe University of California, Berkeley.For more information, please visitwww.excision.bio.

Contact:InvestorsJohn Fraunces - LifeSci Advisors917-355-2395jfraunces@lifesciadvisors.com

MediaRobert Flamm, Ph.D.Burns McClellan, Inc.212-213-0006 ext. 364rflamm@burnsmc.com

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Excision BioTherapeutics Awarded California Institute for Regenerative Medicine (CIRM) Grant to Support Ongoing Phase 1/2 Trial Evaluating EBT-101 as...