Genetics expand at Penn Med

In 2001, Lancelot, a formerly blind dog, went to Washington to shake paws with Congress.

Lancelot was born with PRA — progressive retinal atrophy ­­— but became the first blind animal to gain sight through a gene-therapy trial led by Gustavo Aguirre, a professor of Medical Genetics and Opthalmology at Penn.

It was this work that laid the foundation for a clinical trial in 2007 that would restore partial vision to humans suffering from LCA — Leber congenital amaurosis — another blindness related disease.

Eye diseases are only one of the many diseases — including hemophilia and cancer — that may some day have a cure, due in part to Penn’s deep involvement in the field of gene therapy.

“You could fill up several issues of [The Daily Pennsylvanian] with all of the gene-therapy research Penn has been involved in,” School of Medicine Chief of Staff Susan Phillips said.

HIV is one disease in particular where Penn gene-therapy research is making headway. Findings presented by Carl June on March 2 show the successful alteration of DNA in immune cells to be HIV-resistant in nine patients. Though the study is only in phase one and the results do not imply a cure, “this is probably the best candidate right now for a way to have someone actually get cured of HIV,” June said in a March 21 article of the DP.

David Weiner, a professor of Pathology and Laboratory Medicine, also conducts research on using gene therapy to treat HIV, although he focuses on creating DNA-based vaccines.

Weiner’s work “could totally change the world,” Phillips said.

Gene therapy also shows promise in the treatment of hemophilia.

Medical School professor Katherine High conducted clinical trials in this area in 1999 and 2001. The treatment was able to change hemophilia from a severe to a mild form, although it faded after about ten weeks in humans. High is currently in the “early days” of another clinical trial which so far “looks promising.”

The Delivery Vehicles

“I think what I learned from our early experience is that the technology that was available to us when we started … was not adequate,” said James Wilson — former head of Penn’s Institute for Human Gene Therapy, which was eventually disbanded after the 1999 death of 18-year-old clinical patient Jesse Gelsinger.

In 2001, experimental vectors — viruses that serve as the primary “delivery vehicles” for bringing genes into living cells — ultimately induced tumors in clinical patients being treated for hemophilia.

“There’s a whole science around using the right virus vectors to try to eliminate tumor effects and eliminate other inflammatory effects or other negative consequences of the virus,” Glen Gaulton, professor of Pathology and Laboratory Medicine, said.

Wilson has “developed a whole series of new vectors that are quintessential,” Gaulton said of the technological advancement of treatment.

“The key to successful gene therapy is safe and effective delivery,” Wilson said. “And for genes to be effective, they have to be delivered to specific cells — and not only to specific cells, but into a specific part of the cell.”

Wilson and his lab team have spent the last 20 years developing improved technology for delivering genes into cells. He has identified several different forms of AAV — a small virus with minimal side effects — and developed them as vectors. They produce about 2,000 of these vectors a year to distribute to other labs in over 30 different countries for clinical and laboratory trials.

Animal Models

In addition to vectors, the development of animal models that more closely parallel humans is another important technological advancement in the field of gene therapy.

“One of the most important skills is to be able to recognize what is able to work and what is beyond our capability — understanding what you have in animals and what you are able to move successfully into human models,” High said.

“We have good animal models, which we didn’t really have back in the Gelsinger days,” said Arthur Caplan, the director of Penn’s Center for Bioethics. “Much better animal work is being done prior to work in humans, which always is both prudent and safer.”

John Wolfe — professor of Pathology and Medical Genetics at the School of Veterinary Medicine and founder of genetic research at Penn — explained that the Vet School has the largest collection of animal models in the world, carrying diseases from immuno-deficiency to metabolic disorders.

Facing the Future

Gene therapy “had a kind of overpromising that results would come quickly for patients,” Caplan said. But he added that the deaths of subjects both at Penn and elsewhere led to “a very rough and rocky start” for the field.

However, 20 years since the first clinical trial in 1990, there have been “multiple examples of successful gene therapy that can be pointed to,” High said. “Twenty years is pretty typical for a completely new class of therapeutics.”

Safety concerns over whether or not these diseases are solved better through drugs and other options are ethical challenges Caplan believes gene therapy still faces.

For Wolfe, the main hurdles are continued safety concerns for human trials, finding treatments that extend beyond one disease and the need for continued improvement on developing vectors.

“If it works the way science usually works, then it will probably grow out of some unexpected branch,” Wolfe said. “We’re up against this gauzy curtain of unknown.”

“I think the future of gene therapy is actually strong,” Caplan said, citing its recent intersection with stem cell research. “It is very interesting to watch and very unexpected,” he said. “I mean, nobody could have predicted it.”

“There’s no other institution that has the depth of research and contributions to gene therapy like the faculty have at Penn,” Wilson said. “It’s just amazing and somewhat understated — although I don’t mean to brag.”

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