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Discovery of Gene May Lead to Therapy for a Retinal Disease

Optometrist doing sight testing for senior patient

MSU researchers publish first evidence that the gene mutation causes retinal disease—an early step toward developing treatments for blindness.

One of the leading causes of inherited blindness in humans, retinitis pigmentosa (RP), is analogous to retinal dystrophies that lead to blindness in dogs. Because of their similarities, identifying gene mutations underlying several types of canine retinal dystrophies has suggested courses for research on RP in humans. These advances are significant for both humans and dogs. Discovery of gene may lead to therapy for a retinal disease

The research team that first identified the gene mutation that causes one form of progressive retinal atrophy (PRA) in papillon dogs now has published the first phenotypic evidence that the mutation causes this disease. This evidence is an early step toward developing gene therapies targeting the disease.

Professor Simon Petersen-Jones, Myers-Dunlap Endowed Chair in Canine Health, and PhD candidate Paige Winkler at MSU College of Veterinary Medicine’s Comparative Ophthalmology Lab, in collaboration with Dr. Kari Ekenstedt, Assistant Professor of Animals Genetics at University of Wisconsin-River Falls, were the first team to identify the mutated gene CNGB1 that caused a form of PRA in papillon in June 2011. The team subsequently developed and licensed to OptiGen the first screening test for the gene.

Both PRA and RP are marked by the early loss of rod photoreceptors, which are responsible for night vision. Loss of day vision usually occurs later in both diseases. The team found that the CNGB1 subunit of the rod photoreceptor channel had a mutation in the PRA-affected dogs and resulted in an early onset loss of rod function—as would be anticipated by the gene mutation. The mutation of the CNGB1 gene is considered to be responsible for about 70 percent of papillon PRA.

The research team’s findings were published in the scientific journal PLoS ONE August 19, 2013, following two years of investigation and verification.

“Whenever you see a genetic change, you have to be sure that it’s causing disease,” says Petersen-Jones. “Although this change looked convincing of being disease-causing, we wanted to confirm that the mutation definitely caused that disease.”

Dr. Simon Petersen-JonesThe mutation causes a lack of a normal protein that is necessary for healthy functioning of rod photoreceptors. The researchers verified that the normal protein was not being produced in the retinas of affected dogs.

Using electroretinography, the team measured the electrical responses of the photoreceptors to light stimulus in order to assess retinal function in the affected dogs. The dogs lost function as expected from the lack of protein, and had markedly reduced or absent rod-mediated responses from an early age.

“We now have the evidence in animals that this gene mutation causes the disease,” says Petersen-Jones. “We can show that that there’s no rod response from a very early age—this is what you’d anticipate from the lack of normal protein.”

The team’s discoveries are leading the way and opening doors for research around the world. The genetic mutation identified by Petersen-Jones’ team was subsequently independently identified by a team in Finland.

Moving towards therapeutic solutions for humans and dogs

“The next step is to initiate gene therapy trials,” says Winkler. “We expect to begin these in the coming year. We also will continue to detail the progression of the disease.”

Because of the similarities of this retinal dystrophy in humans and dogs, developments of therapies for dogs may provide an important foundation for preclinical assessment of therapies for human patients. Dogs with retinal dystrophies are valuable models of human retinal disease, and in hold promise for developing treatments for human blindness and for advancing investigations in human patients.

The paper, “A Large Animal Model for CNGB1 Autosomal Recessive Retinitis Pigmentosa,” was published online August 19, 2013 in PLoS ONE.

 — Via College of Veterinary Medicine

— Inset photos: Paige Winkler with papillons that have the CNGB1 mutation (top) and Dr. Peterson-Jones.


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