An inherited form of blindness directly comparable to a common inherited optic nerve disease in humans has been discovered in rhesus macaques at the California National Primate Research Center at the University of California, Davis. The work, published April 15 in Proceedings of the National Academy of Sciences, could lead to a better understanding of autosomal dominant optic atrophy, or ADOA, and potentially to new treatments.
ADOA affects about 3 in 100,000 people worldwide, causing progressive vision loss and eventual blindness. People with the disease develop blind spots, or scotoma, and there is no available treatment, said Sara Thomasy, senior author on the paper. Thomasy is a professor of comparative ophthalmology and holds dual appointments at the Weill School of Veterinary Medicine and the Department of Ophthalmology and Vision Science at UC Davis. Many patients are diagnosed between the ages of 10 and 30 and it is thus a significant cause of vision loss in children.
In humans, ADOA is related to mutations in a gene called OPA1 which affects mitochondria. While mitochondria are found throughout the body, the long nerve axons that run from the retina to the brain are particularly vulnerable to mitochondrial defects.
Rhesus macaques and other non-human primates have a very similar eye structure and vision system to humans. Thomasy and colleagues found that some of the monkeys at the research center had a spontaneous mutation in OPA1 that leads to changes in the eye very similar to those in people with ADOA.
A pandemic project
The discovery came about because first author Tracy Jaggers, then a veterinary student at Western University College of Veterinary Medicine who was planning a summer project with Thomasy, had to switch projects due to the COVID-19 pandemic.
"We had planned this wonderful behavioral study out at the primate center, and then COVID hit and obviously she couldn't come and do the project. So I said, well, I have this interesting data set of monkeys with this mutation," Thomasy said.
The mutation in OPA1 had previously been identified by sequencing the DNA of 1,800 animals at the center as part of a collaboration with Baylor College of Medicine. But it had not been tied to any eye disease.
"It didn't look very obvious to me that there's something going on. I actually expected it to be a negative study," Thomasy said. "But Tracy was so tenacious with the data."
Using imaging techniques from human ophthalmology, Jaggers and Thomasy found that an animal with eye abnormalities also carried a copy of the OPA1 mutation. With that data, they were able to get a grant from the National Eye Institute to expand the research.
"That grant really allowed us to study those individuals and set up a breeding colony," Thomasy said.
The researchers can now look at how the disease progresses over time and how it differs between animals with a single copy or two copies of the OPA1 mutation. The rhesus macaque could be a model to study gene therapy to prevent ADOA, or to test treatments that could slow or block progression in humans, Thomasy said.
Thomasy and colleagues including Ala Moshiri and Glenn Yiu at the Department of Ophthalmology and Vision Science at UC Davis Health have been able to identify equivalents of other human inherited eye diseases in macaques. These include achromatopsia, in which the cone cells responsible for color vision are destroyed, and age-related macular degeneration.
Additional authors on the paper are: at UC Davis, Ana Ripolles-Garcia, Brett Story, Lucy Moore, Jaeho Shim, Ana Raposo, Maria Isabel Casanova, Sophie Le, Sangwan Park, Laura Young, Soohyun Kim, Karolina Roszak, Vanessa Ureno, Paige Karpinen, Nayel Echeverria, Monica Ardon, Brian Leonard, Marguerite Knipe, Eliza Bliss-Moreau and Nicholas Marsh-Armstrong; Jun Wang, Rui Chen, J. Timothy Stout and Jeffrey Rogers, Baylor College of Medicine; Leandro Texeira, University of Wisconsin-Madison; and Brad Fortune, Legacy Devers Eye Institute, Portland, Ore.
The work was supported by grants from the National Institutes of Health.
