Daily Archives: July 18, 2017

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.

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

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