Second Eyes Treated Successfully in LCA Gene Therapy Clinical Trial at Children's Hospital of Philadelphia

February 08, 2012


Drs. Albert Maguire, Katherine High and
Jean Bennett of CHOP

Clinical development of gene therapy for retinal degenerations has taken a big step forward, based on six-month results for three adults whose second eyes were treated in the Foundation-supported Phase I/II trial for people with Leber congenital amaurosis (LCA) at The Children’s Hospital of Philadelphia (CHOP). All three demonstrated improvement in visual and retinal function in their second eyes after treatment, which was administered one-and-a-half to three-and-a-half years after their first eyes were treated. The participants experienced further reductions in nystagmus, the involuntary eye movements common in people with LCA. And re-administration of the gene therapy was safe; no harmful immune reactions were observed.

For trial participant Tami Morehouse, having her second eye treated has been life-changing. Now she can see her children’s faces, watch them play baseball and better appreciate her natural surroundings. She describes the improvement in her vision as “incredible.” The participants also said they can do activities they couldn’t do before, such as walking around at night and shopping for groceries.

The results of the trial were announced by CHOP today, and also reported in the February 8, 2012, online edition of Science Translational Medicine.

“We are delighted to be able to safely and effectively treat both eyes of our patients,” say Dr. Jean Bennett, who co-leads the trial with Dr. Albert Maguire. “But as you can imagine, they are even more delighted. Though these individuals have advanced retinal degeneration, we saw reported improvements in light sensitivity, visual acuity and visual fields in their newly treated eyes. Two of the subjects can now navigate in dimly lit settings. That’s very meaningful for them. Of course, long-term follow-up in these and additional subjects in our study will be important to understand the full safety profile, but we are very excited about these initial results.”

Dr. Stephen Rose, the Foundation’s chief research officer, adds, “This is an important advancement for the retinal gene therapy field. It was critical to verify that a second exposure to the therapy’s viral delivery technology didn’t elicit an immune response that could jeopardize the treatment’s safety and effectiveness. And until now, there was no track record for administration of a second dose in people. Dr. Bennett and her team at CHOP did a great job establishing confidence for re-administration in humans after completing two important large-animal studies of second-eye treatment.”

After treatment of the second eyes, Dr. Manzar Ashtari used functional magnetic resonance imaging (fMRI) to observe activity in each participant’s visual cortex, the part of the brain used for vision. As expected, activity in the region of the brain that processes input from the second treated eye improved. But, remarkably, brain activity for the region corresponding to the initially treated eye also improved.

“We’ve known that our eyes in many ways work together, but this imaging study brings our understanding to a whole new level,” says Dr. Rose. “And it shows how beneficial it can be to treat both eyes.”

Twelve people with LCA caused by mutations in the gene RPE65, including a boy who was 8 years old when treated, are enrolled in the CHOP study, which began in late 2007. The participants, all of whom were virtually blind, demonstrated sustained vision improvement of varying levels after the initial treatment.

Dr. Bennett says that the compelling safety and efficacy data from these first three adult subjects has allowed the team to obtain the necessary regulatory approvals to invite the other study participants to undergo therapy re-administration to the second eye. Dr. Katherine High, the director of the Center for Cellular and Molecular Therapeutics at CHOP, continues to manage the critical regulatory aspects of these groundbreaking studies.

In addition to the CHOP study, Phase I/II clinical trials for LCA (RPE65 mutations) gene therapy are underway at: the Universities of Pennsylvania and Florida, Moorfields Eye Hospital in London, Oregon Health & Science University in Portland, and Hadassah Medical Organization in Jerusalem.