Researchers have developed a gene therapy that successfully treats a form of macular degeneration in a canine model. The work sets the stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision and which is currently untreatable. The study is published in Proceedings of the National Academy of Sciences.
"In the eye, you have these two integral retinal cell layers that puzzle into one another and, like a zipper, they interweave your vision cells and the support cells," Cideciyan says. "What this disease is doing is basically unzipping those layers, and what we've done is rezip them, bringing them together tightly."
"With this research," Guziewicz says, "we have demonstrated that there is a therapy that is working in a large animal model. Following safety studies, a human clinical trial could be less than two years away."
Best disease, or vitelliform macular degeneration, is an inherited blinding disorder caused by mutations in the BEST1 gene. It often manifests in children and young adults, gradually robbing them of their central vision.
Through a variety of studies during the last several years, the Penn team has shown that dogs, too, develop a strikingly similar disease. A 2014 study led by Beltran revealed that dogs, like humans, have a tiny region at the center of their retina that is densely packed with cone photoreceptor cells called a fovea. BEST1 mutations in both humans and dogs compromise the fovea, leading to vision loss.
Based on success treating other blinding diseases, the group has been developing a gene therapy to treat this condition. And working with the canine model, Guziewicz et al. reported last year the discovery of the underlying defect responsible for the disease.
the failure of a supporting structure known as the retinal pigment epithelium, or RPE, to tightly connect to the light-sensing photoreceptor cells. That finding gave the researchers the outcome measures they needed to determine with confidence whether a gene therapy would work.
In the newly published study, the researchers further probed the canine Best disease while also examining human patients with BEST1 mutations to see if analogous defects could be seen.
Examining the retinas of dogs with disease mutations, the researchers found a retina-wide abnormality; the internal surface of the 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 very early, when the affected dogs were only 6 weeks old.
An additional finding that arose when the dogs were examined under light was that light exposure dramatically increased the severity of the RPE-photoreceptor separation. When dogs were returned to darkness, the separation decreased.
Remarkably, they were able to correct both mild and more severe lesions. Close examination of the eyes of treated dogs revealed that the gene therapy restored the "zipper" structure between RPE and photoreceptor cells.
"Since we understand the mechanism of disease better than before," says Guziewicz, "it also allows us to understand the mechanism of rescue. We can visualize these projections extending from the RPE that never existed before; it's incredible. That restored the proper apposition between those two cell layers." The therapy appears to be lasting, as the treated dogs' eyes remained disease-free for as long as five years.
"On a human level, there are a lot of families who know that previous generations have had this disease, and the young people can live in fear of whether it is going to affect them," Jacobson says. "This is the unveiling of a mechanism and a treatment for a previously untreatable form of juvenile or inherited macular degeneration, and that's a major step forward."