RP Gene Therapy Improves Vision After Significant Retinal Degeneration

December 30, 2013

A Foundation-funded research team has developed a gene therapy that restored vision in mice which had lost half of their photoreceptors to autosomal recessive retinitis pigmentosa (arRP) caused by mutations in the gene PDE6α. Results of the study, led by Stephen Tsang, M.D., Ph.D., of Columbia University, were published in the journal Human Molecular Genetics.

Thanks, in part, to this advancement, an international consortium led by Bernd Wissinger, Ph.D., of the University Eye Hospital Tübingen in Germany, was recently formed to move PDE6α gene therapy into a clinical trial.

Previously, a team led by Dr. Tsang showed that gene therapy improved and preserved vision in mice with an early stage of PDE6α-associated arRP before photoreceptor degeneration had occurred. The treatment prevented photoreceptor degeneration for the length of the study, which was 11 months, about half the lifespan of the mice.

However, Dr. Tsang says that most people with arRP caused by PDE6α mutations exhibit the loss of many photoreceptors when they are first examined by an eye-care professional, usually in their late teens or early twenties. Therefore, a human gene therapy for this disease needs to work after significant degeneration has occurred.

His team’s study of PDE6α gene therapy in mice with mid-stage retinal degeneration resulted in preservation of remaining rods, the photoreceptors responsible for peripheral and night vision, and cones, the photoreceptors that provide central vision and the ability to perceive details and colors. Improvements in retinal sensitivity — as measured by an electroretinogram, or ERG — persisted for six months, the length of the study.

PDE6α expresses a protein in rods that plays a key role in phototransduction — the process of converting light into electrical signals sent to the brain, where they are interpreted as vision. In people with most forms of RP, including those caused by PDE6α mutations, the loss of rods eventually leads to degeneration of cones.

Dr. Tsang’s gene therapy was contained in a tiny drop of liquid injected underneath the retinas of the mice. The liquid consisted of healthy copies of PDE6α, which were inserted into a human-engineered adeno-associated virus, or AAV. The AAV was designed to safely and effectively deliver the therapeutic genes into the rods of the mice. AAVs have also performed well thus far in several gene-therapy clinical trials for retinal diseases.

“We are very pleased that Dr. Tsang showed his treatment has potential to work for a stage of disease that is applicable to humans,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “The knowledge gained from his lab research moves us an important step closer to a clinical trial.”