One Health: Vision Loss Treatment for Dogs May Benefit Humans

A novel gene therapy proven to halt vision loss in dogs is believed to have One Health potential. The scientists who developed the therapy, which treats a condition that causes blindness called autosomal dominant retinitis pigmentosa (adRP), are hopeful that their strategy may one day be used to delay or halt vision loss in people with the same disease. Retinitis pigmentosa, the most common inherited form of blindness, affects an estimate 60,000 to 100,000 people in the United States.

“We’ve developed and shown proof-of-concept for a gene therapy for one of the most common forms of retinitis pigmentosa,” said William Beltran, DVM, PhD, a professor of ophthalmology at the University of Pennsylvania School of Veterinary Medicine and lead author of the study. The group’s study has been published in the Proceedings of the National Academy of Sciences.

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Retinitis pigmentosa refers to a group of inherited diseases that damage photoreceptors in the retina, leading to retinal degeneration. Because more than 150 rhodopsin mutations can cause adRP, developing effective therapies has proved challenging. People with adRP caused by mutations in the rhodopsin gene usually possess a mutated copy of the gene that codes for an abnormal rhodopsin protein. The abnormal protein is often toxic and slowly kills the rod cells that allow for vision in low light.

In a study funded by the National Eye Institute, the investigators were able to develop a gene therapy construct that reduces the rod cells’ ability to produce the abnormal rhodopsin. They did so using a technology known as shRNA interference, which introduces genetic material into cells to compensate for abnormal genes or to make a beneficial protein.

For their initial testing, the investigators used dogs with a rhodopsin mutation. Similar to how the disease affects people, dogs slowly lose their rod photoreceptors and thus their vision. In the dogs’ retinas, the gene therapy eliminated about 98% to 99% of both mutated and normal rhodopsin. However, because normal rhodopsin is required for the rods to detect light, the researchers added a “hardened” shRNA-resistant rhodopsin gene to the same vector.

“The problem is balance,” said Alfred Lewin, PhD, a professor of molecular genetics and microbiology at the University of Florida College of Medicine in Gainesville. “We wanted to be sure that every cell that got the shRNA also got the replacement, so we made a single adeno-associated viral vector that did both.”

When the dogs were treated with the combined vector version of the gene therapy, they maintained healthy, functional photoreceptors. Because the vector was designed to produce human rhodopsin, it has the potential to work in humans as well. The treatment prevents photoreceptor loss rather than promoting regeneration, so it may be helpful for patients who have slowly progressing forms of adRP and whose retinas include areas with living rod cells that can be treated.

The investigators hope to start preclinical safety studies within the next 2 years, with the eventual goal of human trials.