Category Archives: Gene Medicine

When Audrey Lapidus 10-month old son, Calvin, didnt reach normal milestones like rolling over or crawling, she knew something was wrong.

He was certainly different from our first child, said Lapidus, of Los Angeles. He had a lot of gastrointestinal issues and we were taking him to the doctor quite a bit.

Four specialists saw Calvin and batteries of tests proved inconclusive. Still, Lapidus persisted.

I was pushing for even more testing, and our geneticist at UCLA said, If you can wait one more month, were going to be launching a brand new test called exome sequencing, she said. We were lucky to be in the right place at the right time and get the information we did.

In 2012, Calvin Lapidus became the first patient to undergo exome sequencing at UCLA. He was subsequently diagnosed with a rare genetic condition known as Pitt-Hopkins syndrome, which is most commonly characterized by developmental delays, possible breathing problems, seizures and gastrointestinal problems.

Though there is no cure for Pitt-Hopkins, finally having a diagnosis allowed Calvin to begin therapy. The diagnosis gave us a point to move forward from, rather than just existing in that scary no-mans land where we knew nothing, Lapidus said.

Unfortunately, there are a lot of people living in that no-mans land, desperate for any type of answers to their medical conditions, saidDr. Stanley Nelson, professor of human genetics and pathology and laboratory medicine atthe David Geffen School of Medicine at UCLA. Many families suffer for years without so much as a name for their condition.

What exome sequencing allows doctors to do is to analyze more than 20,000 genes at once, with one simple blood test.

In the past, genetic testing was done one gene at a time, which is time-consuming and expensive.

Rather than testing one sequential gene after another, exome sequencing saves time, money and effort, saidDr. Julian Martinez-Agosto, a pediatrician and researcher at theResnick Neuropsychiatric Hospital at UCLA.

The exome consists of all the genomes exons, which are the coding portion of genes. Clinical exome sequencing is a test for identifying disease-causing DNA variants within the 1 percent of the genome which codes for proteins, the exons, or flanks the regions which code for proteins.

To date, mutations in the protein-coding parts of genes accounts for nearly 85 percent of all mutations known to cause genetic diseases, so surveying just this portion of the genome is an efficient and powerful diagnostic tool. Exome sequencing can help detect rare disorders like spinocerebellar ataxia, which progressively diminishes a persons movements, and suggest the likelihood of more common conditions like autism spectrum disorder and epilepsy.

More than 4,000 adults and children have undergone exome testing at UCLA since 2012. Of difficult to solve cases, more than 30 percent are solved through this process, which is a dramatic improvement over prior technologies.Thus, Nelson and his team support wider use of genome-sequencing techniques and better insurance coverage, which would further benefit patients and resolve diagnostically difficult cases at much younger ages.

Since her sons diagnosis, Lapidus helped found the Pitt-Hopkins Syndrome Research Foundation. Having Calvins diagnosis gave us a roadmap of where to start, where to go and whats realistic as far as therapies and treatments, she said. None of that would have been possible without that test.

Next, experts at UCLA are testing the relative merits of broader whole genome sequencing to analyze all6 billionbases that make up a persons genome.The team is exploring integration of this DNA sequencing with state-of-the-art RNA or gene expression analysis to improve the diagnostic rate.

The entire human genome was first sequenced in 1990 at a cost of $2.7 billion. Today, doctors can perform the same test at a tiny fraction of that cost, and believe that sequencing whole genomes of individuals could vastly improve disease diagnoses and medical care.

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Genetic sequencing unravels rare disease mysteries - UCLA Newsroom

Philadelphia drug developer Spark Therapeutics said Monday that the Food and Drug Administration has accepted its biologics license application and granted priority review for its lead drug candidate to treat rare inherited blindness.

If approved, the treatment would be the first gene therapy for a genetic disease in the United States.

Sparks treatment, called voretigene neparvovec, streams genes directly into the eyes retina. It has been granted priority review by the FDA because it treats a medical condition where no adequate therapy exists, the company said.

The time frame for possible approval is about six months, around Jan. 12, 2018.

Spark was spun out of Childrens Hospital of Philadelphia, based on decades of research led by Katherine A. High, Sparks co-founder, president, and chief scientific officer.

Its really an exciting moment for medicine, said Spark chief executive officer Jeffrey D. Marrazzo, noting that an FDA panel last week reviewed an experimental T-cell immune therapy being developed by Novartis and the University of Pennsylvania to treat acute lymphocytic leukemia. The original study for the CAR-T cell technology was conductedat Childrens Hospital of Philadelphia, he said.

Spark does not have confirmation, but expects that the FDA may convene an advisory meeting of medical experts in the fall to consider the companys data from three clinical trials, which enrolled 41 participants.

In a late-stage Phase 3 study, 93 percent (27 of 29 participants) had vision improvement and saw restoration of aspects of their functional vision, Marrazzo said.

No serious side effects were reported with the gene therapy itself. Two side effects were reported among 41 participants, due to the surgery, which is an injection in the eye. One participant lost visual acuity, or sharpness of vision. A second participant got a bacterial infection in the eye after the injection.

Patients in an earlier Phase 1 trial have been followed now for four years and continue to maintain their original vision improvement, he added. About 3,500 patients in the U.S. and five large European markets live with the disease. About half, or 1,750, are in the U.S.

Sparks treatment injects particles that are a copy of a normally functioning gene into the back of each eye.

Marrazzo said its too early to set a price. The company hopes the treatment will be a onetime injection, and not a lifetime of treatments, and thus deserves an appropriatepayment.

Were doing a lot of work trying to figure out value of this type of treatment, which could be indicated for restoring sight in kids and adults who otherwise are going to progress to complete blindness, Marrazzo said. Were looking at other rare disease products which are chronically delivered, and whats the value in not having to chronically deliver something for a rare disease.

Spark officials have met with health-care payers, including most large commercial health insurers, to discuss the companys clinical data with the goal of ensuring that patients can have access to the treatment, Marrazzo said. Theres a lot of work still in front of us, but Im very confident and pleased with where we are today in the process.

Spark is also developing treatments for hemophilia A and hemophilia B and for a hereditary retinal degeneration disease, choroideremia, whichusually manifests during childhood in males as night blindness and a reduction of visual field.

Sparks stock closed up $1.29 on Monday, or 2.17 percent, to $60.65.

Published: July 17, 2017 12:22 PM EDT

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Philly biotech's first-ever gene therapy progresses with FDA - Philly.com

Along with David Reich, a geneticist at Harvard Medical School, Dr. Thangaraj led an effort to analyze data from more than 2,800 individuals belonging to more than 260 distinct South Asian groups organized around caste, geography, family ties, language, religion and other factors. Of these, 81 groups had losses of genetic variation more extreme than those found in Ashkenazi Jews and Finns, groups with high rates of recessive disease because of genetic isolation.

In previous studies, Dr. Reich, Dr. Thangaraj and colleagues found that social groups in South Asia mixed between around 4,000 and 2,000 years ago. After that, the solidification of Indias caste system resulted in a shift toward endogamy. You can see writ in the genome the effects of this intense endogamy, Dr. Reich said.

Today, South Asia consists of around 5,000 anthropologically well-defined groups. Over 15 years, the researchers collected DNA from people belonging to a broad swath of these groups, resulting in a rich set of genetic data that pushes beyond the fields focus on individuals of European ancestry, Dr. Reich said.

The scientists then looked at something called the founder effect. When a population originates from a small group of founders that bred only with each other, certain genetic variants can become amplified, more so than in a larger starting population with more gene exchange.

Most people carry some disease-associated mutations that have no effect because theyre present only in one parents genes. In an endogamous group, however, its more likely that two individuals carry the same mutation from a common founder. If they reproduce, their offspring have a higher risk of inheriting that disease.

Rare conditions are therefore disproportionately common in populations with strong founder events. Among Finns, for instance, congenital nephrotic syndrome, a relatively rare kidney disease, is uniquely prevalent. Similarly, Ashkenazi Jews are often screened for diseases like cystic fibrosiss or Gaucher disease.

To measure the strength of different founder events, Dr. Reich and Dr. Thangarajs team looked for long stretches of DNA shared between individuals from the same subgroups. More shared sequences indicated a stronger founder event.

The strongest of these founder groups most likely started with major genetic contributions from just 100 people or fewer. Today, 14 groups with these genetic profiles in South Asia have estimated census sizes of over one million. These include the Gujjar, from Jammu and Kashmir; the Baniyas, from Uttar Pradesh; and the Pattapu Kapu, from Andhra Pradesh. All of these groups have estimated founder effects about 10 times as strong as those of Finns and Ashkenazi Jews, which suggests the South Asian groups have just as many, or more, recessive diseases, said Dr. Reich, who is of Ashkenazi Jewish heritage himself.

The next step, the authors say, is to map out and study the genetic origins of diseases prevalent in different groups. As proof of concept, they screened 12 patients from southern India for a gene mutation known to cause a joint disease called progressive pseudorheumatoid dysplasia. Of the six people that had the mutation, five instances could be traced to founder effects, and one case could be traced to a marriage between close relatives.

This distinction is important because its well documented that marriage between close relatives can increase the possibilities of recessive disease. But many South Asians are not yet aware that they should also look out for genetic risks among broader populations, said Svati Shah, an associate professor of medicine at Duke University who was not involved in the research.

Theres a tendency to think, This will never happen to me because I will never marry my first cousin, Dr. Shah said. But thats not whats happening here, according to the data.

There are many other suspected examples of disease associations that have yet to be systematically studied in South Asia. Some medical caregivers speculate that people with the surname Reddy may be more likely to develop a form of arthritis affecting the spine, Dr. Thangaraj said. Others think people from the Raju community, in southern India, may have higher incidents of cardiomyopathy, which affects the heart muscle.

If recessive disease mutations are cataloged, they could potentially be used for prenatal or premarital screening programs, which can be immensely powerful, said Priya Moorjani, an author of the paper and a postdoctoral researcher at Columbia University.

An example of successful genetic cataloging can be found in Dor Yeshorim, a Brooklyn-based organization that screens Ashkenazi and Sephardi Jews for common disease-causing mutations to inform marriage matchmaking. The program is credited with virtually eliminating new cases of Tay-Sachs disease, a neurodegenerative disorder, from these communities.

Beyond rare diseases, groups with founder effects hold lessons about common diseases and basic biology, said Alan Shuldiner, a professor of medicine at the University of Maryland and a genetics researcher for Regeneron Pharmaceuticals, who was not involved in the study. He and his collaborators have gained new insights into heart disease and Type 2 diabetes, for instance, from studying Old Order Amish.

Scientists often try to manipulate, or knock out, genes in mice or flies to better understand human disease. But populations like those found across South Asia provide a powerful opportunity to study how gene changes manifest naturally in humans. These are genetic experiments of nature that have occurred across the planet, Dr. Shuldiner said.

The sheer number of people and different groups in South Asia means theres a huge, untapped opportunity to do biological and genetic research there, Dr. Reich said.

He suggested that knockouts of almost every single gene in the genome probably exist in India.

I would argue that its unequal to anywhere else, he said.

A version of this article appears in print on July 18, 2017, on Page D3 of the New York edition with the headline: A Living Lab for Inherited Diseases.

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In South Asian Social Castes, a Living Lab for Genetic Disease - New York Times

July 17, 2017 Credit: The District

Gene editing using 'molecular scissors' that snip out and replace faulty DNA could provide an almost unimaginable future for some patients: a complete cure. Cambridge researchers are working towards making the technology cheap and safe, as well as examining the ethical and legal issues surrounding one of the most exciting medical advances of recent times.

Dr James Thaventhiran points to a diagram of a 14-year-old boy's family tree. Some of the symbols are shaded black.

"These family members have a very severe form of immunodeficiency. The children get infections and chest problems, the adults have bowel problems, and the father died from cancer during the study. The boy himself had a donor bone marrow transplant when he was a teenager, but he remains very unwell, with limited treatment options."

To understand the cause of the immunodeficiency, Thaventhiran, a clinical immunologist in Cambridge's Department of Medicine, has been working with colleagues at the Great Northern Children's Hospital in Newcastle, where the family is being treated.

Theirs is a rare disease, which means the condition affects fewer than 1 in 2,000 people. Most rare diseases are caused by a defect in the genetic blueprint that carries the instruction manual for life. Sometimes the mistake can be as small as a single letter in the three billion letters that make up the genome, yet it can have devastating consequences.

When Thaventhiran and colleagues carried out whole genome sequencing on the boy's DNA, they discovered a defect that could explain the immunodeficiency. "We believe that just one wrong letter causes a malfunction in an immune cell called a dendritic cell, which is needed to detect infections and cancerous cells."

Now, hope for an eventual cure for family members affected by the faulty gene is taking shape in the form of 'molecular scissors' called CRISPR-Cas9. Discovered in bacteria, the CRISPR-Cas9 system is part of the armoury that bacteria use to protect themselves from the harmful effects of viruses. Today it is being co-opted by scientists worldwide as a way of removing and replacing gene defects.

One part of the CRISPR-Cas9 system acts like a GPS locator that can be programmed to go to an exact place in the genome. The other part the 'molecular scissors' cuts both strands of the faulty DNA and replaces it with DNA that doesn't have the defect.

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"It's like rewriting DNA with precision," explains Dr Alasdair Russell. "Unlike other forms of gene therapy, in which cells are given a new working gene but without being able to direct where it ends up in the genome, this technology changes just the faulty gene. It's precise and it's 'scarless' in that no evidence of the therapy is left within the repaired genome."

Russell heads up a specialised team in the Cancer Research UK Cambridge Institute to provide a centralised hub for state-of-the-art genome-editing technologies.

"By concentrating skills in one area, it means scientists in different labs don't reinvent the wheel each time and can keep pace with the field," he explains. "At full capacity, we aim to be capable of running up to 30 gene-editing projects in parallel.

"What I find amazing about the technology is that it's tearing down traditional barriers between different disciplines, allowing us to collaborate with clinicians, synthetic biologists, physicists, engineers, computational analysts and industry, on a global scale. The technology gives you the opportunity to innovate, rather than imitate. I tell my wife I sometimes feel like Q in James Bond and she laughs."

Russell's team is using the technology both to understand disease and to treat it. Together with Cambridge spin-out DefiniGEN, they are rewriting the DNA of a very special type of cell called an induced pluripotent stem cell (iPSC). These are cells that are taken from the skin of a patient and 'reprogrammed' to act like one of the body's stem cells, which have the capacity to develop into almost any other cell of the body.

In this case, they are turning the boy's skin cells into iPSCs, using CRISPR-Cas9 to correct the defect, and then allowing these corrected cells to develop into the cell type that is affected by the disease the dendritic cell. "It's a patient-specific model of the cure in a Petri dish," says Russell.

The boy's family members are among a handful of patients worldwide who are reported to have the same condition and among around 3,500 in the UK who have similar types of immunodeficiency caused by other gene defects. With such a rare group of diseases, explains Thaventhiran, it's important to locate other patients to increase the chance of understanding what happens and how to treat it.

He and Professor Ken Smith in the Department of Medicine lead a programme to find, sequence, research and provide diagnostic services to these patients. So far, 2,000 patients (around 60% of the total affected in the UK) have been recruited, making it the largest worldwide cohort of patients with primary immunodeficiency.

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"We've now made 12 iPSC lines from different patients with immunodeficiency," adds Thaventhiran, who has started a programme for gene editing all of the lines. "This means that for the first time we'll be able to investigate whether correcting the mutation corrects the defect it'll open up new avenues of research into the mechanisms underlying these diseases."

But it's the possibility of using the gene-edited cells to cure patients that excites Thaventhiran and Russell. They explain that one option might be to give a patient repeated treatments of their own gene-edited iPSCs. Another would be to take the patient's blood stem cells, edit them and then return them to the patient.

The researchers are quick to point out that although the technologies are converging on this possibility of truly personalised medicine, there are still many issues to consider in the fields of ethics, regulation and law.

Dr Kathy Liddell, who leads the Cambridge Centre for Law, Medicine and Life Sciences, agrees: "It's easy to see the appeal of using gene editing to help patients with serious illnesses. However, new techniques could be used for many purposes, some of which are contentious. For example, the same technique that edits a disease in a child could be applied to an embryo to stop a disease being inherited, or to 'design' babies. This raises concerns about eugenics.

"The challenge is to find systems of governance that facilitate important purposes, while limiting, and preferably preventing, unethical purposes. It's actually very difficult. Rules not only have to be designed, but implemented and enforced. Meanwhile, powerful social drivers push hard against ethical boundaries, and scientific information and ideas travel easily often too easily across national borders to unregulated states."

A further challenge is the business case for carrying out these types of treatments, which are potentially curative but are costly and benefit few patients. One reason why rare diseases are also known as orphan diseases is because in the past they have rarely been adopted by drug companies.

Liddell adds: "CRISPR-Cas9 patent wars are just warming up, demonstrating some of the economic issues at stake. Two US institutions are vigorously prosecuting their own patents, and trying to overturn the others. There will also be cross-licensing battles to follow."

"The obvious place to start is by correcting diseases caused by just one gene; however, the technology allows us to scale up to several genes, making it something that could benefit many, many different diseases," adds Russell. "At the moment, the field as a whole is focused on ensuring the technology is safe before it moves into the clinic. But the advantage of it being cheap, precise and scalable should make CRISPR attractive to industry."

In ten years or so, speculates Russell, we might see bedside 'CRISPR on a chip' devices that screen for mutations and 'edit on the fly'. "I'm really excited by the frontierness of it all," says Russell. "We feel that we're right on the precipice of a new personalised medical future."

Explore further: Testing the efficacy of new gene therapies more efficiently

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Snip, snip, curecorrecting defects in the genetic blueprint - Phys.Org

Circadian rhythm is reflected in human behavior and in the molecular workings of our cells. Now scientists from the Perelman School of Medicine at the University of Pennsylvania have developed a powerful tool for detecting and characterizing those molecular rhythmsa tool that could have many new medical applications, such as more accurate dosing for existing medications.

The tool is a machine learning-type algorithm called CYCLOPS that can sift through existing data on gene activity in human tissue samples to identify genes whose activity varies with a daily rhythm. (The acronym CYCLOPS stands for CYCLic Ordering by Periodic Structure.)

We can take advantage of that information potentially in many ways, for example to find times when it is easier to detect cancers and other diseases, and also to improve the dosing of many existing drugs by changing the time of day they are given, says lead author Ron C. Anafi, MD, PhD, an assistant professor of sleep medicine, in a release.

Described in the Proceedings of the National Academy of Sciences, CYCLOPS at least partly overcomes what has been one of the major obstacles to studying circadian rhythms in humans.

Its just impractical and dangerous to take tissue samples from an individual around the clock to see how gene activity in a particular cell type varies, Anafi says.

CYCLOPS instead is meant to use the enormous amount of existing data on gene activity in different human tissues and cellsdata obtained from people at biopsies and autopsies, in scientific as well as medical settings.

Such data almost never includes the time of day when tissue samples were taken. But CYCLOPS doesnt need to know sampling times. If the dataset is large enough, it can detect any strong 24-hour pattern in the activity level of a given gene, and can then assign a likely clock time to each measurement in the dataset.

In an initial demonstration, Anafi and colleagues used CYCLOPS to analyze a dataset on gene activity levels in mouse liver cellsa dataset for which sampling times were available. The algorithm was able to put data on cycling genes into the correct clock-time sequence even though it had no access to actual sampling times.

The algorithm performed best when restricting its analysis to genes whose activity is known to cycle in most mouse tissuesand under this condition it was able to correctly order samples for all mouse tissues. Focusing on human genes that are related to strongly cycling mouse genes, CYCLOPS also was able to correctly order samples taken from human brains at autopsy. It effectively provided an independent, accurate prediction of the time of death, Anafi says.

Next the researchers used CYCLOPS to generate new scientific data on human molecular rhythms. In a first-ever analysis of human lung and liver tissue, the algorithm revealed the strongly cyclic activity in thousands of lung-cell and liver-cell genes. These included hundreds of drug targets and disease genes.

For many of these genes, the daily variability in activity turned out to be larger than the variability due to all other environmental and genetic factors, says study co-author John Hogenesch, a former professor of Pharmacology at Penn Medicine now at the Cincinnati Childrens Hospital Medical Center.

Underscoring the potential medical relevance of this research, CYCLOPS found strong cycling in several genes whose protein products are targeted by common drugs. In one case, CYCLOPS detected a strong circadian-type rhythm in the activity of the gene for angiotensin converting enzyme (ACE), a protein in lung vessels that is targeted by blood pressure-lowering drugs. Prior studies have found that ACE inhibitor drugs appear to work better at controlling blood pressure when given at night. Our discovery of daily cycling in the ACE gene could explain those findings, Anafi says.

He and his colleagues applied CYCLOPS to liver cell gene activity data, and again found many genes with strong circadian rhythms. Comparing normal liver tissue samples with those from primary liver cancers, they found that about 15% of the normally cycling genes they identified lost their rhythmic activity in the cancerous cellswhich suggests that there are times of day when cancer cells can be more readily targeted while avoiding injury to normal tissue.

One of the strongly cycling genes CYCLOPS detected in liver cells was SLC2A2, which encodes a glucose transporting protein, GLUT2. The pancreatic cancer drug streptozocin interacts with GLUT2 in a way that tends to be toxic to cells that express itsometimes toxic enough to kill patients receiving the drug. Anafi and colleagues showed that by giving mice streptozocin at a time of day when liver GLUT2 levels are lowest, they were able to significantly reduce the drugs toxicity, without impairing its ability to hit its intended targets.

Anafi and his colleagues are now using CYCLOPS to generate an atlas of cycling genes in different human tissues, in order to find other drugs whose dosing could be optimized by altering the time of day they are given.

The researchers also plan to use CYCLOPS to study gene activity cycling in cancerous cells, which could one day enable doctors to detect cancers more sensitively as well as to optimize the dosing of cancer therapies.

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Circadian Rhythm Algorithm Could Lead to More Effective Dosing for Many Existing Drugs - Sleep Review

July 17, 2017 First author Kaity Sliger, PhD, and corresponding author Paul Thomas, PhD, member of the Department of Immunology, examine liquid nitrogen samples. Credit: Peter Barta / St. Jude Children's Research Hospital

Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism that explains the elevated risk and offers clues about the broader anti-viral immune response.

St. Jude Children's Research Hospital led the research, which appears as an advance, online publication today in the scientific journal Nature Medicine.

Researchers screened 393 flu patients ranging from infants to 70 years old. Patients with a particular inherited variation in the gene IFITM3 were more than twice as likely to develop severe, life-threatening flu symptoms as those who carried the protective version of the gene.

Working at the molecular level, the investigators showed how expression of the IFITM3 protein was reduced in killer T cells of patients with the high-risk variant compared to other patients. Researchers also found more killer T cellswhich help patients fight the infectionin the upper airways of flu patients with the protective variant compared to other patients.

"A genetic marker of flu risk could make a life-saving difference, particularly during severe flu outbreaks, by helping prioritize high-risk patients for vaccination, drug therapy and other interventions," said corresponding author Paul Thomas, Ph.D., an associate member of the St. Jude Department of Immunology. "These results raise hopes that this newly identified IFITM3 variant might provide such a marker."

Estimated U.S. flu-related deaths in recent years have ranged from 12,000 to 56,000, according to the U.S. Centers for Disease Control and Prevention. Factors like age, obesity, pregnancy and such chronic health conditions as asthma, chronic lung disease and heart disease are associated with an elevated risk of flu complications and death. However, there are no proven genetic markers of flu risk with an established mechanism of action.

IFITM3 is an anti-viral protein that helps to block flu infection of lung cells and to promote survival of the killer T cells that help clear flu infection in the airways. Previous research from other scientists had reported an association between another IFITM3 variant (rs12252) and flu severity in Han Chinese patients. The underlying mechanism has remained unclear, and the rs12252 variant is rare in individuals of European ancestry.

Thomas and his colleagues began this study by searching for other possible IFITM3 variants that correlated with gene expression, levels of the IFITM3 proteins and were common in flu patients in the U.S. The search led to an IFITM3 variant known as rs34481144.

Researchers screened three different groups of U.S. flu patients and found those with the high-risk version of IFITM3 rs34481144 were likely to become infected with flu more rapidly and to develop more severe symptoms than those with another variant. For example, researchers checked 86 children and adults in Memphis with confirmed flu infections and found two-thirds of patients with the most severe symptoms carried at least one copy of the newly identified high-risk IFITM3 variant. The high-risk variant was found in just 32 percent of patients with milder symptoms.

Researchers also found an association between the newly identified high-risk variant and severe and fatal flu infections in 265 critically ill pediatric flu patients hospitalized in one of 31 intensive care units nationwide. The patients did not have health problems that put them at high risk for severe flu. Of the 17 patients in this group who died from the infection, 14 carried at least one copy of the newly identified high-risk variant. "When we looked at patients of European descent who died, they all carried at least one copy of the high-risk variant," Thomas said.

The predictive value of the newly identified IFITM3 variant is now being studied in flu patients in other countries.

The newly identified variation is found in the region of IFITM3 involved in regulation of gene expression through the binding of proteins and other chemicals that promote or suppress gene activity. Working in the laboratory, researchers showed how binding of proteins like CTCF, which can suppress gene activity, differed between the high-risk and protective variants.

Further study revealed how binding differed between the high-risk and protective variants. Those differences led to lower levels of the IFITM3 protein in ndividuals with two copies of the high-risk gene variant compared to other patients, researchers said. The Memphis flu patients also had fewer of the killer T cells in their upper airways.

"While this research focused on flu infections, the mechanism we identified has implications for regulating many genes involved in anti-viral activity," Thomas said. "CTCF has gained prominence in recent years as a master regulator of genomic organization. Evidence in this study suggests the high-risk variant we identified may be part of a larger network of CTCF binding sites involved in regulation in other genes with anti-viral activity."

Explore further: Genetic variant linked to overactive inflammatory response

More information: E Kaitlynn Allen et al, SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans, Nature Medicine (2017). DOI: 10.1038/nm.4370

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Newly identified genetic marker may help detect high-risk flu patients - Medical Xpress

Things are about to speed up dramatically in genetic research, with scientists developing a new technique that can clone thousands of genes in a single reaction.

The new technology, called a LASSO probe, could be used to create libraries of proteins from DNA samples, speeding up the search for new drugs by replacing the tedious methods of gene cloning currently used.

When you think of cloning you may think of Dolly the sheep or the company that promises to clone your favourite pet so you don't have to live sad and alone, but that's a different kind of cloning. Here we're talking about molecular cloning, a natural process that occurs when bacteria, insects, or plants reproduce without a partner.

Scientists clone DNA because they want to do one of two things; either they want to gain information about a particular gene or they want to manipulate genetic information in a cell to give the cell a new property. Both reasons require scientists to have millions of copies of the same DNA molecule in a test tube.

At the moment, to work out what a gene does by cloning its DNA and expressing its protein is done one gene at a time. The standard sequencing method, called molecular inversion probes, involves capturing small fragments of DNA (about 200 base pairs long) and connecting them together to map out the full genome code.

Weaving together these small sections of code to form the full gene sequence isn't easy, but there hasn't been any other way to sequence long fragments of DNA and it's been holding research back.

Not to scale. Credit: Jennifer E. Fairman/Johns Hopkins University

"We think that the rapid, affordable, and high-throughput cloning of proteins and other genetic elements will greatly accelerate biological research to discover functions of molecules encoded by genomes and match the pace at which new genome sequencing data is coming out," says one of the team, Biju Parekkadan, from Rutgers University.

In this new study, the LASSO probe - which stands for "long adaptor single stranded oligonucleotide" - can capture and clone thousands of long DNA fragments and the researchers hope that the new technique will push the limits of what we can currently do.

"Our goal is to make it cheap and easy for any researcher in any field to clone and express the entire set of proteins from any organism," said co-researcher Ben Larman from Johns Hopkins University School of Medicine. "Until now, such a prospect was only realistic for high-powered research consortia studying model organisms like fruit flies or mice."

How does this new technique work?

A collection of LASSO probes were used to grab desired DNA sequences, you can think of it like the way a rope lasso is used to capture cattle. Instead of aiming for the spiky horns of a cow, the LASSO probe targets a DNA sequence up to a few thousand base pairs long - the typical length of a gene's protein code.

The study is a proof of concept, with the LASSO probes used to capture over 3,000 DNA fragments from the E. coli bacterial genome. The results show the probes successfully captured around 75 percent of the gene they targeted.

There were also other benefits to the LASSO probe technique.

The researchers say that the sequences are captured in a way that allows them to also analyse what the genes' proteins do and demonstrated this by giving antibiotic resistance to a cell that would otherwise be killed by the antibiotic.

The researchers were also able to capture and clone a protein library from a human microbiome sample and they hope that it will lead to improved precision medicine and rapid discovery of new medicines for a range of diseases.

"We're very excited about all the potential applications for LASSO cloning," said Larman. "Our hope is that by greatly expanding the number of proteins that can be expressed and screened in parallel, the road to interesting biology and new therapeutic biomolecules will be dramatically shortened for many researchers."

The study has been published in Nature Biomedical Engineering.

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Scientists Can Now Clone Thousands of Genes in a Single Reaction - ScienceAlert

Radiation therapy (RT) remains a mainstay of modern oncologic treatment, with more than half of all patients receiving RT during their treatment course. However, individual responses to RT vary widely among disease types and patient populations.[1] Recent years have been marked by the development and expanded use of precision medicine in cancer therapeutics. Precision medicine refers to the tailoring of treatment to the individual characteristics of each patient, based on inherent susceptibilities. Although enormous strides have been made in tailoring a variety of approaches to systemic therapy, the role of radiation oncology in precision medicine is just beginning to emerge.[1]

Precision in RT has been advancing along multiple parallel paths. There have been improvements in the precision of anatomic target delineation with the use of intensity-modulated RT, volumetric arc therapy, and stereotactic RT, all of which allow for improved target dose conformality. Concurrent with technical advances in treatment delivery, the field of radiogenomics, or the interplay between genomic elements and radiation response at the cellular level, continues to evolve. Indexing the determinants of radiation response at the cellular level has the potential to allow for more personalized delivery of RT and to further increase the therapeutic ratio of our treatment.[1]

As the rates of cancer survival continue to improve, the effect of treatment toxicity on normal tissue will play an increasingly important role in treatment selection. Capturing patient-reported outcomes from the growing and evolving survivor population sheds light on the potential far-reaching impact of radiogenomics beyond traditional survival measures. Specifically, by recognizing the connection between genotypic variation and normal tissue response, our ability to predict severe toxicities following RT may spare selected individuals from significant morbidity and mortality following treatment.[2] Moreover, studies investigating genetic assays predictive of tumor radiosensitivity may be complementary to studies evaluating the radiosensitivity of noncancerous tissue.[3] The purpose of the current article is multifold: Herein, we will review the background and history of genomic predictors of RT response; evaluate candidate genes and polymorphisms dictating responses to radiation; discuss emerging data on the use of genetic signatures; and review current guidelines on the use of genomic predictors to tailor therapy. The article is structured to discuss outcomes and toxicities based on precision medicine in RT within each of these sections.

Biomarkers have long been used in the field of oncology as an adjunct to traditional staging information to estimate treatment outcomes. In this field of study, it is important to distinguish between prognostic and predictive biomarkers. Prognostic markers are associated with a clinical outcome, such as overall survival (OS), regardless of the treatment delivered.[4] For example, the prostate-specific antigen (PSA) has been proven to be an important biomarker in prostate cancer, correlating with the risk of recurrence and OS. Although elevated PSA levels are associated with worse outcomes, measurement of PSA alone does not yet predict the patient response to specific treatments.

Predictive markers, on the other hand, are indicators of the likely benefit following specific treatment. These markers are therefore useful in tailoring treatment decisions. An example of a predictive marker is ERBB2 gene amplification (resulting in overexpression of human epidermal growth factor receptor 2 [HER2]) in breast cancer, since clinical outcomes are improved by the addition of trastuzumab to the chemotherapy regimen in patients with this genetic aberration.[4] The National Comprehensive Cancer Network (NCCN), in updating the NCCN Biomarkers Compendium, recently released a task force report addressing the use of molecular biomarkers in six major disease sites.[5] While prognostic biomarkers provide important information regarding clinical outcome, implicit to the goal of precision medicine is the identification of predictive biomarkers to help direct individual treatment. Despite the significant progress made by radiogenomics in this regard over the past 20 yearsfrom focused gene studies to genome-wide association studies (GWAS)in the field of radiation oncology, clinical translation of these principles remains a goal on the horizon.[2]

Studies investigating variable responses of tissues to RT date back more than 60 years ago to the investigations carried out by Gray and colleagues.[6-8] Specifically studied was the effect of oxygenation on RT response. The tumor microenvironment has been demonstrated to have topographic variability; certain regions possess particularly low extracellular pH, low nutrient content, and hypoxia. Given the often tortuous and malformed vasculature of tumors, blood flow to the microenvironment contributes to an imbalance in the supply of and demand for oxygen. The resulting hypoxia correlates with tumor cell radioresistance, since the maximal effect of RT is achieved by the generation of free radicals.[6] Preceding the early discovery of the effect of hypoxia on radioresistance was the demonstration of individual variation in the response of normal tissue following treatment with a given dose of radiation. This was first formally described in 1936 with the publication of the now well-described sigmoid doseresponse curve.[9] Alongside the discovery of differing individual responses to similar radiation doses was the detection of RT hypersensitivity in patients with certain rare genetic syndromes. The first such documented adverse reaction occurred in a 10-year-old patient with mutation of the ATM gene, who died from complications related to radiation toxicity in normal tissues. Since this initial case was reported, the ATM mutation has been intricately linked with the DNA damage response and studied extensively.[10] While the demonstration of radiosensitivity in patients with rare genetic disorders has been instrumental in our understanding of differential radiation responses, it does not yet explain the wide range of radiation responses seen in patients without known genetic syndromes.

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The Role of Genomic Techniques in Predicting Response to Radiation Therapy - Cancer Network

Alzheimers disease now affects one out of every eight people over the age of 65 and approximately one in 1,000 people between the ages of 30 and 49. In some segments of our society, such as NFL football players, the rates are even more staggering, with the disease affecting one in 53 NFL retirees between the ages of 30 to 49 (the equivalent of one player per team).

With the total number of people affected by Alzheimers predicted to quadruple within the next 40 years, we need to find a new offensive against this unrelenting disease before it steals the minds of yet another generation. Predictive medicine provides us with a new, highly effective battle strategy that empowers us over Alzheimers. Using predictive medicine, we can now wage a new offensive against this, and many other diseases.

Until now, Alzheimers has been generally thought of as an incurable, unstoppable force of nature that strikes fear in the hearts of all. Patients in my own predictive medicine practice often tell me that they want to undergo comprehensive genetic screening in order to learn their risk for everything ... except Alzheimers disease. When I ask why, the answer is invariably, Because theres nothing I can do about it anyway.

In truth, however, by instituting preventive measures as early as possible, we can significantly lower our risk of contracting Alzheimers disease so that it strikes much later or not at all. A necessary part of the process of becoming empowered over Alzheimers is first realizing that many preventive measures do exist and that we can effectively lower our risk. We are not powerless against this disease.

Contrary to what most people believe, Alzheimers is not a disease of old age. It is a disease that develops slowly throughout our lives. While we may not notice the symptoms until we are much older, it starts to attack the proper functioning of our brain decades before any symptoms appear. Because of this, lifelong preventive measures are warranted.

Predictive medicine, a revolutionary new field that combines genetic technology with proactive, personalized prevention, allows us to assess risk and institute prevention of Alzheimers, even in children. By conducting comprehensive genetic testing we can not only find out whether you are at risk for hundreds of diseases, including Alzheimers, but, more importantly, determine which preventions will be most effective in lowering your risk of contracting those diseases.

Predictive medicines goal is to enable you and your physician to institute genetically tailored prevention years or even decades before disease occurs. No more waiting for disease - no more waiting for suffering. With predictive medicine, you can protect yourself against disease while you are still healthy and strong.

Predictive medicines strategy in defeating Alzheimers is straightforward: first, we use genetic screening to identify those individuals who are at increased risk; second, for those who are at increased risk, we use further genetic analysis to determine the most effective forms of prevention; and third, we institute these genetically tailored preventive measures throughout the persons life, starting as young as possible.

With a simple, relatively low-cost test requiring only some saliva (no needles, no blood), we can now predict who is at risk for Alzheimers and what will be the most effective methods of prevention against it. While there are many preventive strategies we can use against Alzheimers (all of which I discuss in my book, Outsmart Your Genes) one of the most powerful is actually quite simple: the avoidance of head injury.

We all contain a specific gene that helps the brain heal after injury, but approximately one in seven people contain changes within this gene, causing it to malfunction and rendering the brain less able to heal itself effectively following injury. While people with this abnormal gene have an increased risk of Alzheimers disease, their risk of the disease actually skyrockets if they suffer a head trauma such as a concussion. In these individuals, head injury is tantamount to throwing fuel onto a fire.

So finding out that you or your children have this abnormal gene provides the incentive for you to institute measures that will prevent the occurrence of significant head trauma. This might mean choosing not to play contact sports and/or making sure to always wear a helmet when rollerblading or biking.

Unfortunately, head injury is much more common than most people think, especially amongst high school, college and professional athletes. For example, more than 1 million teenagers play high school football, and a survey conducted in 2007 by The New York Times found that close to 50 percent of these athletes reported suffering one concussion, and 35 percent reported having sustained multiple concussions in a single season.

A 2010 Time magazine article also found that at the end of a single season, more than 70 percent of college football players reported concussion-like symptoms. And these numbers dont take into account the head injuries suffered while playing other contact sports, including boxing, ice hockey and wrestling.

The link between head trauma and an increased risk of Alzheimers has already become evident to members of the National Football League, which recently started a program called the 88 Plan to provide yearly monetary compensation to retired players who are suffering from Alzheimers. Preliminary results from a study now being conducted by the University of Michigan show that the rate of Alzheimers disease may be as much as 20 times higher in football players than in the general population. The numbers are so startling, in fact, that the US House Judiciary Committee convened a hearing several years ago to investigate the association between head injuries in the NFL and diseases of the brain, including Alzheimers.

By proactively limiting head injury throughout the life of those people who contain the abnormal gene that puts them at increased risk, we can significantly lower their risk of Alzheimers. And that is just one of the many genetically tailored preventive measures we can put into practice to battle this disease.

We no longer have to accept Alzheimers as inevitable. We no longer have to fear growing older. Genetic testing and predictive medicine gives us the ability to go forward knowing that we can control our own destiny. We can and we will win this war against Alzheimers. Through the use of genetic technology, we will prevail.

About The Author: Brandon Colby MD is the Founder of Sequencing.com, the worlds largest App Store for DNA. Dr. Colby created Sequencing.com for people who have already had genetic testing, such as from 23andMe, Ancestry.com and National Geographic, and want to continue to obtain valuable insights from their genetic data. While Dr. Colby invented the first set of apps, the App Store now contains dozens of apps that analyze genetic data and provide clear, personalized solutions for better health. Dr. Colby is also the author of Outsmart Your Genes, the definitive laymans guide to the revolutionary fields of genomics and predictive medicine (also known as precision medicine). For additional information, please visit Sequencing.com.

An earlier version of this story was published by Dr. Colby in 2011.

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Waging a New Offensive in Our War Against Alzheimer's Disease - HuffPost

Lexington Herald Leader

Counseling can help you decide whether to get genetic testing Lexington Herald Leader The Centers for Disease Control and Prevention reports that nearly 300,000 women in the United States are diagnosed with breast cancer each year. Certain gene mutations can increase the risk of developing breast cancer and certain other cancers, and ...

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Counseling can help you decide whether to get genetic testing - Lexington Herald Leader