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Statement on Clinical Trial of Gene Transfer Therapy for Childhood-Onset Blindness

November 1, 2007

The National Eye Institute (NEI) of the National Institutes of Health (NIH) is supporting a phase I clinical trial to assess the safety of gene transfer in treating people with a form of Leber congenital amaurosis (LCA). People with the LCA condition are born with severe visual impairment or develop vision loss early in childhood. The trial is now underway and is being conducted by investigators at the University of Pennsylvania and at the University of Florida.

Beneath the retina of the eye lies a single layer of cells called the retinal pigment epithelium (RPE). These cells help to maintain the health and function of the light-sensing rod and cone photoreceptor cells that adjoin the RPE. In 1993, scientists working at NEI discovered a protein within the RPE that they named RPE65. This protein is now known to play a key role in processing vitamin A in the visual cycle in the retina. RPE65 is critical for regeneration of photoreceptor cell visual pigment following exposure to light.

LCA impairs the function of the photoreceptor cells. NEI and NEI-supported researchers have found that one form of LCA is caused by mutations in the RPE65 gene. People with RPE65-associated LCA are unable to produce the normal RPE65 protein and as a result the visual cycle is disrupted. This deprives the photoreceptor cells of functional visual pigment and makes them unable to respond to light.

Although vision loss is severe in this form of LCA, the structure of the retina remains relatively intact for decades before the photoreceptor cells degenerate. This feature of the disease provides a window of opportunity for the development of therapies that could overcome or compensate for RPE65 gene defects.

The proof-of-concept for gene transfer as a treatment for LCA has been demonstrated by NEI-supported investigators in a dog breed that has LCA and also in rodent models of the disease that were created in the laboratory. Retinal function has been restored in these animal models by delivery of the normal RPE65 gene to the retina. Restoration of visual function in affected dogs, in particular, has been remarkable and has persisted for more than five years following a single treatment.

The investigators have conducted rigorous pre-clinical safety studies in animals, including demonstrating the safety of the procedure in non-human primates. With this pre-clinical work completed successfully, the investigators received approval for a human clinical trial from the U.S. Food and Drug Administration and from the NIH Recombinant DNA Advisory Committee. This human trial will evaluate the use of a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina. An independent data and safety monitoring board is providing careful oversight for all aspects of this trial. Potential risks are discussed with prospective participants as part of an extensive screening and informed consent process.

This phase I clinical trial for LCA will better define the safety of this procedure and the study agent. If successful, it will enable investigators to assess the effectiveness of this gene transfer therapy for RPE65-associated LCA and may lead to further clinical trials to establish effectiveness. The expectation and hope is that transferring the RPE65 gene will enable the RPE to produce enough normal RPE65 protein to re-establish regeneration of photoreceptor cell visual pigment following exposure to light, and thereby restore useful visual function in people with LCA.

The Investigators include Samuel G. Jacobson, M.D., Ph.D., Shalesh Kaushal, M.D., Ph.D., William W. Hauswirth, Ph.D., Barry J. Byrne, M.D., Ph.D., Artur V. Cideciyan, Ph.D. and Tomas S. Aleman, M.D.