An aye for a healthy eye

Gene therapies that replace or supplement dysfunctional genes with functioning copies are seen as a promising treatment avenue for inherited retinal diseases (IRDs), which affect over five million people globally. Such therapies could help slow the degeneration of the eye's photoreceptor cells — the rods and cones that sense light. A vector, typically the adeno-associated virus (AAV), delivers the therapeutic gene into the cell with short segments of DNA called promoters.

The promoters help ensure that gene expression is limited to photoreceptors and is robust enough to have a therapeutic effect, even when those cells are unhealthy, explains Raghavi Sudharsan, Research Assistant Professor of Experimental Ophthalmology at the School of Veterinary Medicine, University of Pennsylvania. Most promoters are tested in healthy tissue or early disease. As retinal degeneration progresses, the transcriptional landscape of the photoreceptors changes significantly, which can affect how well such external promoters can function, she says. The activity of GRK1, one of the most widely used promoters, drops significantly in the advanced stages of the disease when the cellular machinery ceases to function optimally. "That makes it less suitable for patients diagnosed later, which is unfortunately quite common," she says.

Now, a team led by Sudharsan has developed four novel promoters that maintain strong and specific activity in advanced degeneration. The study was published in Molecular Therapy (bit.ly/IRD-promoters) in May 2025. Besides their efficacy, such strong promoters also allow for smaller doses of the AAV vectors, reducing the risk of toxicity, Sudharsan says.

To start with, the researchers focused on photoreceptor-specific genes whose expression remains relatively stable even as retinal degeneration advances. "...If a gene continues to be expressed in diseased cells, its promoter might also retain activity under those same conditions," says Sudharsan, the study's lead author. Using this approach, they identified and tested several novel promoters in healthy and degenerating canine retinas. From this panel, they isolated two promoters specific to cones and rods, respectively. She says they also found two compact promoters that drive robust expression in both photoreceptor types. As AAVs have limited packaging capacity, compact promoters leave more room for the therapeutic gene. The researchers have begun to use these promoters in ongoing studies of gene replacement and neuroprotective therapies in degenerating retinas.

The function and specificity of promoters in gene therapy are as important as the target genes themselves, says Indumathi Mariappan, Research Scientist at Hyderabad's L V Prasad Eye Institute, who was not involved in the study. "Such advancements in vector development will advance precision gene therapy."