Radical Gene Therapy Treatment Tackles Eye Disease

University of Pennsylvania research created an impressive success rate for its latest gene therapy treatment.
Shelby Rogers
Close-up shot of an eye with retinis pigmentosa mid-stageChristian Hamel / Wikipedia Creative Commons

Gene therapy continues to be one of the most exciting medical advancements in recent years. A team from the University of Pennsylvania have yet another gene therapy element they've tackled with success. 

The UPenn researchers created a gene therapy treatment for retinis pigmentosa, a genetic disorder that leads to trouble seeing during the night and slowly robs patients of their peripheral vision. If the disorder worsens too much, it would lead to tunnel vision or complete blindness, although complete blindness isn't that common. 

A team from Penn's School of Veterinary Medicine and Perelman School of Medicine collaborated with the University of Florida to create a gene therapy that gets rid of rhodopsin -- a light-sensing molecule. It essentially destrpoys a  copy of the molecule and restores it with a healthy copy of that proteitn. 

What's better is that the team applied the research to a variety fo different genetic makeups. This means more people from a diverse genetic background can potentially be treated using the therapy regardless of how the disease manifests itself.

The full study appears in this week's Proceedings of the National Academy of Sciences

"It's a one treatment fits all," said William A. 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," Beltran continued. "That gives us great hope about making this a translational treatment."

This treatment is one the researchers have been pursuing for years, they noted in a press release.

This particular type of gene therapy has been something that piqued researchers' interest for years, and the results are thanks to a lengthy partnership between experts. 

"We've known for decades that this specific molecule causes a specific form of retinitis pigmentosa, but developing a treatment has not been straightforward," said Artur V. Cideciyan, research professor of ophthalmology at Penn Medicine and co-lead author. "Now, with these elegant results based on years of study in dogs we can start working toward treating these mutations and prevent deterioration of photoreceptor cells in humans."

First, the researchers had to confirm that the condition was caused by rhodopsin mutations.

"In our investigations, we've seen people in the 1990s with this genetic type of retinitis pigmentosa and now we're seeing their grandchildren also affected," Jacobson says. "It's a multi-generational disease and it's a serious disease."

There are a variety of rhodopsin mutations that lead to this discovery. Several mutations result in a toxic 'gain-of-function,' which produces a protein harmful to certain cells in the eye. In order to stop that damage, the researchers developed a strategy for removing the protein.

"We've developed in the past gene therapies for other conditions where the mutation causes a loss of function," said Aguirre, "so in these cases we just needed to add back the normal copy of the gene in order for the photoreceptors to regain their normal structure and function. When you have a dominant disease like this one, where the gene product is really damaging to the cell, you have to get rid of it."

The new study takes all previous research several steps farther.


"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."

At the time of this writing, the team is still trackign the treatment more than eight months after the gene therapy took place. Everything appears to be lasting, the team reported. The next step involves clinical trials.

"The current work has strong implications for the treatment of patients with autosomal dominant retinitis pigmentosa due to Class B rhodopsin mutations," Cideciyan said.

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