Academia, Gene Therapy, Scientific

A knockdown-and-replace gene therapy from Penn researchers shows promise in rare eye disease

It’s been a year of great strides in gene therapy, with Spark’s Luxturna earning the first US regulatory approval in the field for inherited blindness. Now, researchers at University of Pennsylvania might be able to add to that success with a new gene therapy that’s shown promise tackling a group of eye problems called retinitis pigmentosa.

This rare condition changes how the retina responds to light, making it hard for people to see — especially affecting night vision and peripheral vision. And it gets worse over time, sometimes leading to near-blindness. Scientists have identified more than 150 mutations of the light-sensing molecule rhodopsin, which all lead to the disease. However, those researchers at Penn intend to develop a treatment that works regardless of the mutation. They’ve published their early-stage findings in this week’s Proceedings of the National Academy of Sciences.

“It’s a one treatment fits all,” says William Beltran, professor of ophthalmology and director of the Division of Experimental Retinal Therapies at Penn Vet and co-lead author of the study. “The treatment targets a region of the rhodopsin gene that is homologous in humans and dogs and is separate from where the mutations are located. That gives us great hope about making this a translational treatment.”

The researchers, from Penn’s School of Veterinary Medicine and Perelman School of Medicine, collaborated with scientists at the University of Florida to develop a therapy that basically knocks down the abnormal copy of rhodopsin and then replaces it with a healthy copy. This method has worked in dogs, they say, which can develop a very similar disease as humans.

“What we showed was that if you just did the knockdown alone, you preserve the outer nuclear layer of rods, which is where the cell bodies are located,” Beltran said. “But without another critical layer, the outer segments, where rhodopsin plays the essential role of capturing light and initiating vision, then the rods become useless. However, if you combine the knockdown with the replacement reagents, then the drastic difference is that you now have perfectly formed and aligned outer segments and functional photoreceptor cells.”

So far, tracking the treatment effect more than eight months after delivery of the gene therapy, the effect seems stable and lasting. The research team is currently working to move the findings into clinical trials.

Artur Cideciyan, research professor of ophthalmology at Penn Medicine, was the co-lead author of the study.

Image: William Beltran, Artur Cideciyan, Gustavo Aguirre, and Samuel Jacobson were part of the joint team from Penn Vet and Penn Medicine who led the work. PENNVET

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