Monthly Archives: September 2014

PUBLIC RELEASE DATE:

9-Sep-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine http://www.twitter.com/PennMedNews

PHILADELPHIA - Hoping to encourage sufficient investments by pharmaceutical companies in expensive gene therapies, which often consist of a single treatment, a Penn researcher and the chief medical officer of CVS Health outline an alternative payment model in this month's issue of Nature Biotechnology. They suggest annuity payments over a defined period of time and contingent on evidence that the treatment remains effective. The approach would replace the current practice of single, usually large, at-point-of-service payments.

"Unlike most rare disease treatments that can continue for decades, gene therapy is frequently administered only once, providing many years, even a lifetime, of benefit," says James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania. "Under current reimbursement policies, private insurers and the government typically pay for this therapy once: when it is administered. But these individual payments could reach several million dollars each under current market conditions. We're proposing a different approach that spreads payments out and only keep coming if the patient continues to do well."

Wilson and co-author Troyen A. Brennan, MD, JD, MPH, chief medical officer of CVS Health, note that while large single payments for gene therapy may be the simplest approach, they carry substantial encumbrances. For example, approval of gene therapy treatments is unavoidably based on data derived from trials carried out over several years at most -- considerably shorter than the expected duration of the therapy. Payers may therefore be unwilling to pay large up-front sums for treatments whose long-term benefit has not been established. Additionally, large payments for medications, such as the $84,000-a-patient cost of the hepatitis C treatment Sovaldi, have been criticized in the prevailing climate of curbing health care costs. This, despite the fact that effective gene therapy may reduce the overall financial burden to the health care system.

Wilson and Brennan further note that while a liver transplant, for example, can cost up to $300,000, physicians and hospitals that "transplant livers know they will be compensated at market rates through existing contracts -- gene developers lack that assurance." Annuity payments, they say, could help address these problems.

An example of an annuity-type disbursement could be a hypothetical payment of $150,000 per year for a certain number of years for gene-therapy-based protein replacement for patients with hemophilia B -- so long as the therapy continues to work. According to the authors, the cumulative amount should be less than the cost of a one-time payment of $4-6 million, which would be the expected rate for a gene-based therapy to be comparatively priced to existing, conventional therapies for hemophilia B. "One would presume," they write, "that gene therapy will have to represent a discount in order for insurers to approve its use."

"The annuity model that we're proposing would eliminate the misguided incentive to invest in drugs and treatments with ongoing revenue streams but which require continuing, perhaps lifetime daily administration, with all the attendant inconveniences and burdens to patients and their families, as well as direct and indirect costs to the nation's health system," says Wilson.

The authors point out that gene therapy differs substantially from the case of "orphan" drugs. Development of the latter, which target rare diseases affecting small patient populations, is supported by the Orphan Drug Act of 1983, which provides pharmaceutical manufacturers with grants, tax credits, and an extended period of market exclusivity for their medications. What's more, in virtually all of these cases, the business costs of developing the drugs are further attenuated by ongoing administration of -- and payment for -- the medication over the lifetime of the patient. "The contrast with gene therapy, especially that which produces a durable cure with one administration," the authors write, "is clear."

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Penn researcher and CVS Health physician urge new payment model for gene therapy

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Newswise New York, NYSeptember 9, 2014Led by Itsik Peer, associate professor of computer science at Columbia Engineering, a team of researchers has created a data resource that will improve genomic research in the Ashkenazi Jewish population and lead to more effective personalized medicine. The team, which includes experts from 11 labs in the New York City area and Israel, focused on the Ashkenazi Jewish population because of its demographic history of genetic isolation and the resulting abundance of population-specific mutations and high prevalence of rare genetic disorders. The Ashkenazi Jewish population has played an important role in human genetics, with notable successes in gene mapping as well as prenatal and cancer screening. The study was published online on Nature Communications today.

Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes, says Peer, who is also a co-chair of the Health Analytics Center at Columbias Institute for Data Sciences and Engineering, as well as a member of its Foundations of Data Science Center. With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations.

To help in his hunt for disease genes, Peer founded The Ashkenazi Genome Consortium (TAGC) in September 2011 with Todd Lencz, an investigator at The Feinstein Institute for Medical Research, director of the Laboratory of Analytic Genomics at the Zucker Hillside Hospital, and associate professor of molecular medicine and psychiatry at the Hofstra North Shore-LIJ School of Medicine. The other TAGC members, who are providing expertise in the diseases they are studying, are: Gil Atzmon, associate professor of medicine and genetics, Albert Einstein College of Medicine (genetics of longevity and diabetes); Lorraine Clark, associate professor of clinical pathology and cell biology and co-director, Personalized Genomic Medicine Laboratory, Columbia University Medical Center, Laurie Ozelius, associate professor at Icahn School of Medicine at Mount Sinai, and Susan Bressman, chair of neurology at Mount Sinai Beth Israel (Parkinsons disease and related neurological phenotypes); Harry Ostrer, professor of pathology, genetics, and pediatrics, Albert Einstein College of Medicine (radiogenomics, cancers and rare genetic disorders); Ken Offit, chief of clinical genetics at Memorial Sloan Kettering Cancer Center (breast, ovarian, colon and prostate cancers, lymphoma); Inga Peter, associate professor of genetics and genomic sciences, and Judy Cho, professor of medicine and professor of genetics and genomic sciences, both at The Mount Sinai Hospital(inflammatory bowel disease); and Ariel Darvasi, vice-dean of The Faculty of Life Sciences at The Hebrew University of Jerusalem (multiple diseases).

Before the TAGC study, data was available for a limited number of DNA markers (only approximately one in every 3000 letters of DNA) that are mostly common in Europeans. The TAGC researchers performed high-depth sequencing of 128 complete genomes of Ashkenazi Jewish healthy individuals. They compared their data to European samples, and found that Ashkenazi Jewish genomes had significantly more mutations that had not yet been mapped. Peer and his team analyzed the raw data and created a comprehensive catalog of mutations present in the Ashkenazi Jewish population.

The TAGC database is already proving useful for clinical genomics, identifying specific new mutations for carrier screening. Lencz explains: TAGC advances the goal of bringing personal genomics to the clinic, as it tells the physician whether a mutation in a patients genome is shared by healthy individuals, and can alleviate concerns that it is causing disease. Without our work, a patients genome sequence is much harder to interpret, and more prone to create false alarms. We have eliminated two thirds of these false alarms.

The TAGC study further enables more effective discovery of disease-causing mutations, since some genetic factors are observable in Ashkenazi individuals but essentially absent elsewhere. Moreover, the demography of the Ashkenazi population, the largest isolated population in the U.S., enables large-scale recruitment of study patients and hence more genetic discoveries than in other well-known isolated populations like the Amish and Hutterites locally, or the Icelanders overseas. The researchers expect that medical insights from studies of specific populations will also be relevant to general populations as well.

The TAGC teams findings also shed light on the long-debated origin of Ashkenazi Jews and Europeans. The genetic data indicates that the Ashkenazi Jewish population was founded in the late medieval times by a small number, effectively only hundreds of individuals, whose descendants expanded rapidly while remaining mostly isolated genetically.

Our analysis shows that Ashkenazi Jewish medieval founders were ethnically admixed, with origins in Europe and in the Middle East, roughly in equal parts, says Shai Carmi, a post-doctoral scientist who works with Peer and who conducted the analysis. TAGC data are more comprehensive than what was previously available, and we believe the data settle the dispute regarding European and Middle Eastern ancestry in Ashkenazi Jews. In addition to illuminating medieval Jewish history, our results further pave the way to better understanding European origins, millennia before. For example, our data provides evidence for todays European population being genetically descendant primarily from late mid-eastern migrations that took place after the last ice age, rather than from the first humans to arrive to the continent, more than 40,000 years ago.

Originally posted here:
Mapping the DNA Sequence of Ashkenazi Jews

Researchers from the UNC School of Medicine have discovered that the protein RBM4, a molecule crucial to the process of gene splicing, is drastically decreased in multiple forms of human cancer, including lung and breast cancers. The finding, published today in the journal Cancer Cell, offers a new route toward therapies that can thwart the altered genetic pathways that allow cancer cells to proliferate and spread.

"Historically, scientists haven't targeted the proteins in cancer cells that are involved in gene splicing," said Zefeng Wang, PhD, associate professor in the department of pharmacology and senior author of the Cancer Cell paper. "This is a whole new ballgame in terms of gene regulation in cancer."

There are approximately 25,000 genes in the human genome -- the same amount as in a fruit fly. But in humans, these genes are spliced together in different ways to create various kinds of messenger RNA to produce the many different proteins humans require. It's like a filmmaker splicing together bits of movie scenes to create alternative cuts of a movie. In genetics, this process is called alternative splicing.

Wang's lab found that RBM4 is an important film editor.

Wang, a member of the UNC Lineberger Comprehensive Cancer Center, studies how alternative splicing happens in normal cells and in cancer cells. Through a series of biochemical experiments and high-throughput screening methods, his team identified about 20 proteins that are involved in regulating alternative splicing. Then his team conducted further experiments to pinpoint changes in the activity of these proteins in various kinds of human cancer cells and in mouse models. Such "misregulated" protein expression would provide evidence that the proteins are involved in cancer development or metastasis.

Wang found that the protein RBM4 was decreased, as compared with normal tissue. In lung and breast cancer patients, RBM4 was drastically "down regulated."

"In normal cells, RBM4 inhibits alternative splicing," Wang says. "It makes genes splice from a long form into a short form. For one of the genes we study, which is called Bcl-x, we want the short form because it has anti-cancer properties."

When RBM4 is low, the longer form of Bcl-x is produced, which plays a role in promoting cancer development and metastasis. "In mouse models, we showed that activating RBM4 can reverse cancer progression," Wang said.

Wang's group also found that RBM4 played a role in controlling another splicing regulator called SRSF1, which is highly expressed in some cancer cells. "What's interesting is that RBM4 actually inhibits the expression of SRSF1 and therefore controls the splicing of many SRSF1 targets in an opposite fashion. This again showed us why RBM4 has activity as a tumor suppressor.

Wang said that RBM4 is needed in the proper amount so that these genes are spliced properly and don't contribute to cancer development and metastasis. This means that the level of RBM4 in cancer patients can actually be used to predict their chances of survival.

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New genetic target for a different kind of cancer drug found