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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

Using a new cellular model, innovative gene therapy approaches for the hereditary immunodeficiency Chronic Granulomatous Disease can be tested faster and cost-effectively in the lab for their efficacy. A team of researchers ...

Scientists have developed a new approach to repair a defective gene in blood-forming stem cells from patients with a rare genetic immunodeficiency disorder called X-linked chronic granulomatous disease (X-CGD). After transplant ...

Researchers at Queen's University have published new findings, providing a proof-of-concept use of genetic editing tools to treat genetic diseases. The study, published in Nature Scientific Reports, offers an important first ...

A team from the Center for Genome Engineering, within the Institute for Basic Research (IBS), succeeded in editing two genes that contribute to the fat contents of soybean oil using the new CRISPR-Cpf1 technology: an alternative ...

In recent years, science and the media have been buzzing with the term CRISPR. From speculation around reviving the woolly mammoth to promises of distant cures for cancer, the unproven potential for this genome editing tool ...

Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

Large tubeworms living in the cold depths of the Gulf of Mexico may be among the longest living animals in the world. This is revealed in a study in Springer's journal The Science of Nature. According to lead author Alanna ...

Scientists at the University of Washington have discovered a simple way to raise the accuracy of diagnostic tests for medicine and common assays for laboratory research. By adding polydopaminea material that was first ...

It's not quite E=mc2, but scientists unveiled Monday a simple, powerful formula that explains why some animals run, fly and swim faster than all others.

The red algae called Porphyra and its ancestors have thrived for millions of years in the harsh habitat of the intertidal zoneexposed to fluctuating temperatures, high UV radiation, severe salt stress, and desiccation.

Invasive plant species can be a source of valuable ecosystem functions where native coastal habitats such as salt marshes and oyster reefs have severely declined, a new study by scientists at Duke University and the University ...

In zebra finches, sperm velocity and morphology and hence reproductive success strongly depend on a specific mutation (an inversion) on one of the sex chromosomes, called Z. This was discovered by scientists of the Max Planck ...

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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