Major federal grant awarded to UF-led effort to treat inherited form of blindness

The National Institutes of Health has awarded a $9.8 million grant to scientists seeking to use gene therapy to reverse a form of inherited blindness.

The funds, from the NIH’s National Eye Institute, will support researchers at the University of Florida, the University of Pennsylvania and Cornell University as they prepare to test the therapy in people born with a gene mutation that causes Leber congenital amaurosis.

LCA is a currently untreatable condition that typically results in blindness from birth or shortly thereafter. A small clinical trial to test the therapy in about 20 adults likely will begin in two to three years.

“This will be the first time gene therapy will be tested for a retinal disease, setting the stage for trying such techniques in many other eye diseases that affect millions of people in the United States,” said William W. Hauswirth, Ph.D., the grant’s principal investigator and the Rybaczki-Bullard professor of ophthalmic molecular genetics at UF’s College of Medicine.

“The therapy worked so beautifully in dogs that it makes sense to move toward trying it in people,” said Hauswirth, who is affiliated with the Vision Research Center, the Powell Gene Therapy Center and the Genetics Institute, all of UF.

Hauswirth and his collaborators garnered national attention when they reported in the May issue of the journal Nature Genetics that they had restored eyesight in three Briard dogs by injecting healthy copies of the RPE65 gene into light-sensitive cells of the retina. The gene is needed to produce a protein that helps translate light waves into nerve impulses that the brain interprets as images.

An estimated 2,000 people in the United States have a mutation of the RPE65 gene that results in LCA. Mutations of other genes are linked to thousands of additional LCA cases. Efforts are under way to develop gene therapy to combat those other mutations.

The new grant will support a variety of projects involved in preparing for or beginning clinical tests. At UF, these include efforts to improve the vector, or carrier molecule, that will be used to transport healthy gene copies into the eyes of clinical trial participants. The vector is a genetically modified version of the apparently harmless adeno-associated virus. AAV dwells problem-free in most people and has never been known to cause illness.

UF scientists will work to develop a highly purified form of AAV suitable for use in people. They also will try to improve the vector’s efficiency so they can effectively treat eyes with the lowest possible number of viral particles. UF is home to the nation’s only academic center with facilities for producing human-grade AAV.

At Penn and Cornell, testing of the therapy will continue in mice and dogs.

“We’re taking a very conservative approach as we prepare for the clinical trial,” Hauswirth said. “Our main consideration is safety.”

In an added step to protect patients, an independent panel appointed by NIH will scrutinize the research at various stages.

“Their job will be to make sure we’re meeting all of our benchmarks regarding safety and efficacy before we move on to the next step,” Hauswirth said.

Meanwhile at Penn, researchers will begin evaluating patients for possible inclusion in the clinical trial. Only adults will participate in the initial study, but infants and children also will be examined in light of potential benefits from the therapy in years to come.

“We need to begin with patients old enough to give informed consent for themselves, which is normally thought to be people 18 and over,” Hauswirth said. “But if we can demonstrate that there is no toxicity associated with the therapy, we can petition to push the window of testing to younger patients, because those patients should in theory have a better chance of benefiting.”

Researchers expect they will find “a window of treatability” because patients’ photoreceptor cells begin to die away through the course of the disease. That cell loss is not reversible through this sort of gene therapy, Hauswirth said.

Samuel G. Jacobson, M.D., Ph.D., director of the Center For Hereditary Retinal Degeneration at the University of Pennsylvania’s Scheie Eye Institute and the clinical principal investigator on the grant, noted that part of the patient evaluation process will involve determining whether each potential research participant has the form of LCA caused by a mutation of the RPE65 gene. Edwin Stone, M.D., Ph.D., of the University of Iowa, will be the key co-investigator responsible for this effort.

Albert M. Maguire, M.D., of the University of Pennsylvania, will be the surgeon responsible for delivering therapy to patients at the Scheie Eye Institute.

“Our role at Penn will be to examine the patients, devise special vision tests for these patients, measure their vision before treatment, follow them through the clinical trial and then measure their vision after treatment to decide whether the therapy is doing any good,” Jacobson said. “We’ll also make sure there are no adverse effects. That kind of vigilance is critical.”

Other contributors to the research include Terence R. Flotte, M.D., director of UF’s Genetics Institute; Jean Bennett, M.D., Ph.D., and Artur V. Cideciyan, Ph.D., of the University of Pennsylvania; and Gustavo D. Aguirre, Ph.D., V.M.D., and Gregory M. Acland, B.V.Sc., at Cornell.

The research effort also is supported by grants from the Foundation Fighting Blindness, Research to Prevent Blindness and the Macular Vision Research Foundation.

For more information regarding participating in the clinical trial, call Dr. Jacobson at the Scheie Eye Institute at (215) 662-9981 or e-mail chrd@uphs.upenn.edu.