When scientists embark on developing a treatment for an inherited retinal disease, one of their first tasks is to identify or create a model of the condition. Disease models can be cells in a Petri dish, a genetically engineered mouse or rat, or larger animal such as a pig. Each type of model has its pros and cons, including cost and similarity of disease characteristics to those in humans.
The investigators then use the model to study how vision is lost — that is, they figure out which types of retinal cells degenerate, what is causing the degeneration, and how quickly the cells stop working. After they gain an understanding of the disease, researchers evaluate potential therapeutic approaches using the model as a testing platform.
The goal: Move a therapy into a human study.
University of Pennsylvania researchers funded by the Foundation recently identified a canine model of Leber congenital amaurosis (LCA) caused by mutations in the gene NPHP5. In humans, the condition causes early and severe vision loss from LCA, and in some cases, kidney dysfunction. The investigators found that in canines, the retinal degeneration is remarkably similar to that in humans with NPHP5 mutations, though dogs don’t have the renal dysfunction. The investigative team included: Gus Aguirre, V.M.D., Ph.D., and William Beltran, V.M.D., Ph.D., at the School of Veterinary Medicine (Penn Vet), as well as Samuel Jacobson, M.D., Ph.D., and Artur Cideciyan, Ph.D., at Scheie Eye Institute.
Using the model, Dr. Aguirre and his colleagues are now testing potential gene therapy approaches to eventually slow or halt vision loss, or possibly improve vision, in humans. They’ve already had some success in canines.
“In both humans and dogs with NPHP5 mutations, there is early loss of rods. Cones survive, but have severely impaired function,” says Dr. Aguirre. “In our initial NPHP5 gene therapy studies in canines, we were able to preserve vision and retinal structure at an early stage of disease.”
(Cones are the photoreceptors that provide central vision, and the ability to perceive details and colors. Rods provide peripheral vision, and the ability to see in dim and dark settings.)
Over the last two decades, Penn Vet has made major contributions to the advancement of therapies for inherited retinal diseases having established more than two dozen canine models, including those for: X-linked retinitis pigmentosa, Best disease, cone-rod dystrophy, and achromatopsia. It was Dr. Aguirre and his colleagues who identified a dog breed with RPE65 mutations — including the world-famous canine Lancelot — which helped launch RPE65 gene-therapy clinical trials. Thanks to the success of one of those studies, Spark Therapeutics is now seeking regulatory approval for its RPE65 gene therapy.
Dr. Aguirre notes that LCA caused by NPHP5 mutations is a ciliopathy, a form of disease that is seen in some other inherited retinal degenerations. Specifically, what Penn Vet is learning from the NPHP5-mutant canines may have implications for understanding and treating LCA caused by CEP290 mutations, which is similar in its manifestation to LCA caused by NPHP5 defects.