Blind World Magazine

Leber Congenital Amaurosis.
New Gene Therapy Emerging for LCA Caused by RPGRIP Mutation.

August 09, 2005.
By Ben A. Shaberman,
The Foundation Fighting Blindness (FFB).

FFB-funded researchers from the Berman-Gund Laboratory, Harvard Medical School, Massachusetts Eye and Ear Infirmary have developed a gene replacement therapy to rescue photoreceptors in mice with a type of Leber congenital amaurosis (LCA) caused by a mutation in the RPGRIP gene. LCA is a severe, early onset form of retinitis pigmentosa (RP).

“Because LCA strikes people at an early age and affects their vision substantially, we are pleased with this advancement,” says Stephen Rose, Ph.D., Chief Research Officer, Foundation Fighting Blindness. “It’s an important step toward a clinical trial for a devastating retinal disease.”

To date, researchers have identified eight genes that cause different types of LCA. They believe more LCA-causing genes are yet to be discovered.

Rose notes, “This gene therapy treats a type of LCA that is different from the LCA gene therapy that’s moving into a human clinical trial, and gave vision to Lancelot and 50 other dogs born blind. The dogs have a mutation in a different gene known as RPE65. With this new advancement, which treats the RPGRIP mutation, we’re making good progress in overcoming another type of LCA, and ultimately, treating more people.”

In healthy retinas, the RPGRIP protein is present in the cilia of photoreceptors. Cilia — which perform critical functions in many organs including the ear, lung, and kidneys — are “tiny hairs” called microtubules. They provide a critical, conveyor-like transport mechanism for proteins and other substances. In the normal retina, the cilia move proteins such as opsin through the photoreceptor, from a region known as the inner segment to the tip of the photoreceptor, also known as the outer segment. If the cilia don’t work correctly, because the RPGRIP protein is absent, opsin is not transported to the outer segments of photoreceptors. The result is an adverse affect on the visual process and retinal degeneration.

Tiansen Li, Ph.D., and his colleagues tested their RPGRIP gene replacement therapy in mice that lacked the RPGRIP gene. An adeno-associated virus (AAV), a safe, man-made virus, was used to deliver a normal RPGRIP to the photoreceptors. The treatment rescued photoreceptors, and also gave the mice normal retinal function as measured by electroretinograms (ERGs).

A research paper on this advancement is being published in the September issue of the journal Investigative Ophthalmology & Visual Science.

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