Penn researchers have developed a gene therapy that treats a form of macular degeneration in a canine model, setting the stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision that is currently untreatable.
The study, published in Proceedings of the National Academy of Sciences, was led by Karina E. Guziewicz, a research assistant professor in Penn’s School of Veterinary Medicine, and Artur V. Cideciyan, a research professor of ophthalmology in the School of Medicine. Collaborators included vision scientists from Penn Vet’s Division of Experimental Retinal Therapies, Gustavo D. Aguirre, professor of medical genetics and ophthalmology, William Beltran, professor of ophthalmology, and from Penn Medicine Samuel G. Jacobson, professor of ophthalmology.
Best disease, or vitelliform macular degeneration, is an inherited blinding disorder caused by mutations in the BEST1 gene. The Penn team has previously shown that dogs develop a similar disease. Examining the retinas of dogs with disease mutations, they found a retina-wide abnormality; the internal surface of the retinal pigment epithelium (RPE), critical for communication with the light-sensing photoreceptor cells, failed to develop normally, preventing the photoreceptors from coming into close contact. This could be detected when the affected dogs were only 6 weeks old.
They also found light exposure dramatically increased the severity of the RPE-photoreceptor separation. When returned to darkness, the separation decreased. It’s unknown whether this association is present in human patients, but they took steps to show that a similar separation between RPE and photoreceptors is affecting vision. By measuring the time it took for patients to adjust to darkness, the researchers obtained a proxy for the time it takes for nutrients to diffuse between these two layers of cells.
“This flow of nutrients normally occurs over a very small distance,” Dr. Cideciyan says. “So if you have a separation between these two layers, the recovery rate to get night vision slows down. The implication is that, if we could correct the apposition of these two tissues, we would correct the visual defect as well.”
That is what the researchers set out to do in testing the gene therapy construct. Using a harmless viral vector, they injected a healthy copy of the BEST1 gene, using either the canine or human version of the gene, into the dogs with the canine version of Best disease, at early- and middle-disease stages. Remarkably, they were able to correct both mild and more severe lesions.
Work remains to be done before embarking on human clinical trials, but given the closeness with which dogs recapitulate the human disease, the researchers are hopeful that the findings will translate.