Correcting night blindness in dogs.

Correcting night blindness in dogs.
People with congenital stationary night blindness (CSNB) are unable to distinguish objects in low light conditions. This impairment presents challenges, especially when artificial lighting is not available or when driving at night.
In 2015, researchers at Penn's School of Veterinary Medicine discovered that dogs can develop a form of hereditary night blindness with strong similarities to the condition in people. In 2019, the team identified the gene responsible.
Today, in the journal Proceedings of the National Academy of Sciences , they reported a major breakthrough: a gene therapy that restores night vision to dogs born with CSNB. The success of this approach, which targets a group of cells deep in the retina called ON bipolar cells, represents a significant step toward the goal of developing a treatment for dogs and people with this condition, as well as other vision problems that involve ON bipolar cell function.
Dogs with CSNB that received a single injection of the gene therapy began to express healthy LRIT3 protein in their retinas and were able to deftly navigate a maze in low light. The treatment also appears long-lasting, with a sustained therapeutic effect lasting a year or more.
"The results of this pilot study are very promising," says Keiko Miyadera, lead author of the study and assistant professor at Penn Vet. "In people and dogs with congenital stationary night blindness, the severity of the disease is consistent and unchanged throughout their lives. And we were able to treat these dogs as adults, between 1 and 3 years of age. That makes these findings promising and relevant to the human patient population, because theoretically we could intervene even in adulthood and see an improvement in night vision."
In previous work, the Penn Vet team, working in collaboration with groups from Japan, Germany and the United States, discovered a population of dogs with CSNB and determined that mutations in the LRIT3 gene were responsible for the dogs' impaired night vision. The same gene has also been implicated in certain cases of human CSNB.
This mutation affects the function of ON bipolar cells, but unlike some diseases that cause blindness, the overall structure of the retina as a whole remained intact. This gave the research team hope that providing a normal copy of the LRIT3 gene could restore night vision to affected dogs.
However, while Penn Vet researchers in the Division of Experimental Retinal Therapies have developed effective gene therapies for a variety of other blindness disorders, none of these previous treatments have targeted the ON bipolar cells, located deep in the middle layer of the retina.
"We have entered the retinal no-man's land with this gene therapy," says William A. Beltran, coauthor and Penn Vet professor, "This opens the door to treating other diseases that affect ON bipolar cells."
The researchers overcame the hurdle of reaching these relatively inaccessible cells with two main discoveries.
First, through a rigorous screening process performed in collaboration with colleagues at the University of California, Berkeley led by John Flannery and the University of Pittsburgh led by Leah Byrne, they identified a vector for the healthy LRIT3 gene that would allow the treatment to reach the intended cells. And second, they paired the healthy gene with a promoter - the gene sequence that helps initiate the "reading" of the therapeutic gene - that would act in a cell-specific way.
"Previous therapies we've worked on have targeted photoreceptors or cells of the retinal pigment epithelium," says coauthor Gustavo D. Aguirre, a professor at Penn Vet. "But the promoter we use here is very specific for targeting ON bipolar cells, which helps avoid potential off-target effects and toxicity."
The researchers suspect that restoring the functional LRIT3 gene allows signals to pass from photoreceptor cells to ON bipolar cells. " LRIT3 is expressed in the 'fingertips' of these cells," Beltran says. "Introducing this transgene is essentially allowing the two cells to shake hands and communicate again."
"We had great success in this study, but we saw some dogs recover better than others," says Miyadera. "We would like to continue working to maximize the therapeutic benefit while still ensuring safety. And we saw that this treatment is durable, but does it last a lifetime after one injection? That's something we'd like to find out."
The team also plans to alter the therapy to use the human version of the LRIT3 gene , a necessary step to translate the treatment to people with CSNB with an eventual clinical trial.