Gene Therapy for Leber Congenital Amaurosis

Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood

George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology

Human adeno-associated virus (AAV) was discovered.

Dr. George Wald, Harvard University, received The Nobel Prize in Physiology or Medicine for his discovery of the role of vitamin A in the visual process

Drs. Nicolas Muzyczka and Paul Hermonat, University of Florida, published an article demonstrating that adeno-associated virus (AAV) can be used to introduce foreign DNA into human and murine tissue culture cells.

Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation cloned RPE65, a protein necessary for processing vitamin A in the visual cycle

RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis

The knockout mouse model was created by Dr. T. Michael Redmond's team in the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation and established RPE65's role in vitamin A metabolism

RPE65 gene mutation was discovered as causing congenital blindness in Briard dogs

NEI-supported researchers at the University of Pennsylvania and University of Florida restore vision in a Briard dog using gene transfer RPE65 therapy

NEI/NIH expands support for pre-clinical studies of RPE65 gene therapy development

Restored vision in Briard dog persists longer than four years following RPE65 gene transfer

NEI-supported RPE65 human clinical trial began (open label, single dose, dose escalation study) to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina

• Principal Investigator: Dr. Sam Jacobson, University of Pennsylvania
• Principal Investigator: Dr. Barry Byrne, University of Florida
• Gene Vector Specialist: Dr. William Hauswirth, University of Florida
• Surgeon: Dr. Shalesh Kaushal, University of Florida

In September, results from the NEI-supported RPE65 human clinical trial published in Human Gene Therapy and Proceedings of the National Academy of Sciences USA. There were no vector-related serious adverse events or systemic toxicities detected in the three patient who were treated. Visual acuity was not statistically different from baseline. All patients self-reported increased visual sensitivity in the study eye compared to their control eye, especially noticeable in dim light.