The effectiveness of gene therapy for Leber congenital amaurosis (LCA) peaked within one to three years after treatment before diminishing, according to data published yesterday from three of the 15 patients treated for the inherited vision disorder in an ongoing clinical trial.

In findings published in The New England Journal of Medicine, investigators at the Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, found that improvement in the three patients’ vision was maintained over five to six years following treatment with a single administration of the vector containing the gene RPE65.

In these patients, according to the study, “the treated retina showed improved visual sensitivity, which slowly increased in area and then contracted.”

The study added: “We observed a subsequent decline in the area of improved sensitivity in all patients; the decline in Patient 3 occurred earlier than in the other patients.” That patient showed improvement faster too—over the course of a year, compared with 1 to 3 years in Patient 2, and over three years for Patient 1.

“This study shows that the current therapy doesn't appear to be the permanent treatment we were hoping for,” acknowledged the study’s lead author Samuel G. Jacobson, M.D., Ph.D., professor of ophthalmology and director of the Center for Hereditary Retinal Degenerations and Retinal Function Department at Scheie Eye Institute. “But the gain in knowledge about the time course of efficacy is an opportunity to improve the therapy so that the restored vision can be sustained for longer durations.”

Jacobson and co-investigators Artur V. Cideciyan, PhD, research professor of ophthalmology at Penn and William W. Hauswirth, PhD, professor of ophthalmology at the University of Florida at Gainesville, began the gene therapy clinical trial in 2007. During the trial, people with LCA received retinal injections of a virus engineered to deliver instructions to the retina to produce a healthy version of the gene RPE65.

Within days of the injections, some patients reported increases in their ability to see dim lights they had never seen before. Researchers also found that four of the 15 patients started relying on the fovea, an area of the retina with a high density of photoreceptors located near the gene therapy injection, for seeing letters. Typically, the fovea is reserved for seeing fine details.

The early results were hailed at the time as significant: “It is hugely encouraging to see that gene-replacement therapy for RPE65 can be effective, even in adults who have severely advanced disease,” James W.B. Bainbridge, Ph.D., and Robin R. Ali, Ph.D., of University College London wrote in a 2008 commentary in the journal Gene Therapy.

Yet Drs. Bainbridge and Ali cautioned: “The questions relating to the duration for which visual improvement is maintained in the human participants, and whether further retinal degeneration is slowed, can be addressed only after several years.”

In the latest study, Dr. Jacobson and colleagues found that the treated regions of the three patients studied not only gained in visual sensitivity in the early months after therapy, but saw an unexpected increase in efficacy over many years. However, the peak improvement was followed by a subsequent long-term decline in efficacy, with the research team reporting it confirmed earlier findings of an “unrelenting” loss of the photoreceptors in the retina in both the previously treated and untreated areas—as well as a diminishing thickness of the photoreceptor layers.

“Our earlier results and these new measurements showed that photoreceptors continued to die at the same rate as they do in the natural course of the disease, regardless of treatment,” Dr. Jacobson said in the statement. “We've been able to positively alter and extend the visual life of patients with LCA, and we now have to develop workable strategies for extending it even further.”

He said the findings of the latest study suggested several potential strategies for improving the outcome of gene therapy. Among options, according to Dr. Jacobson, are staging the disease prior to gene therapy to clarify potential benefits for each individual; guiding the treatment to retinal areas that contain enough functional photoreceptors to respond; launching a second round of gene therapy; and combining gene therapy with other medications designed to improve the functioning of the visual cycle or protect the retina from loss of cells.

RPE65-associated Leber’s congenital amaurosis now joins the many medical diseases for which the consideration of treatment algorithms may be helpful in initiating a dialogue about the emerging complexity and optimization of management,” the study concluded.

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