New Gene Therapy Tools Target Advanced IRDs

Researchers from the University of Pennsylvania’s School of Veterinary Medicine (Penn Vet) have developed a novel gene therapy toolkit targeting inherited retinal degenerations (IRDs) at mid-to-late stages—addressing a critical gap in treatment options for patients diagnosed after significant retinal damage has already occurred. The findings were recently published in Molecular Therapy.

IRDs and the Limitations of Existing Therapies

Inherited retinal degenerations (IRDs) are a group of genetic conditions that cause the progressive loss of vision due to the degeneration of photoreceptors, the light-sensitive cells in the retina. These disorders arise from mutations in genes required for photoreceptor survival and function.

While gene therapy has emerged as a promising approach—by replacing or supplementing defective genes—most current strategies are optimized for early-stage intervention, when many photoreceptors are still intact. This leaves patients diagnosed at later stages with few effective options.

A New Toolkit Tailored for Degenerating Retinas

Led by Dr. Raghavi Sudharsan, Assistant Professor of Experimental Ophthalmology, and Dr. William A. Beltran, the Corinne R. Henry Bower Endowed Professor of Ophthalmology, the Penn Vet team has developed four novel photoreceptor-specific promoters designed to remain active in retinas already affected by significant degeneration.

“These short segments of DNA act as molecular ‘switches’ to turn on the therapeutic gene in target cells, driving strong and specific gene expression in rod and cone photoreceptors even in mid-to-late stages of disease,” explained Dr. Sudharsan.

Outperforming Existing Promoters

In direct comparisons, the new promoters significantly outperformed the widely used GRK1 promoter in both expression strength and cell specificity. Unlike conventional promoters—most of which are tested only in healthy models—the new candidates were validated in degenerating retinal environments.

“The newly developed promoters were selected for their ability to remain active even when more than half of the photoreceptors had been lost,” noted Sudharsan. “This makes them more applicable to the clinical realities faced by many IRD patients.”

Spotlight on GNGT2-Based Promoters

Among the novel promoters tested, GNGT2-based sequences demonstrated particularly robust expression in both rods and cones, even at advanced disease stages. Notably, their small size—under 850 base pairs—makes them compatible with adeno-associated virus (AAV) packaging, an essential requirement for efficient gene delivery.

The researchers also highlighted the high photoreceptor specificity of the new promoters, which may help minimize off-target effects and reduce immune responses, key factors in improving safety and long-term therapeutic efficacy.

Clinical Relevance and Validation

To develop these promoters, the team employed a multi-pronged approach that combined:

• Transcriptomic analysis

• In silico modeling

• In vivo screening in large-animal models

Promoters derived from genes including GNGT2, IMPG2, and PDE6H showed strong, cell-specific expression when delivered via AAVs into canine models that closely mimic human IRDs.

“These findings highlight the importance of testing promoters in clinically relevant models and at appropriate disease stages,” said Dr. Beltran, who also directs the Division of Experimental Retinal Therapies. “This is not something that can be accurately replicated in cell cultures or organoids.”

Toward a New Generation of Gene Therapies

The research lays the groundwork for a new class of gene therapies that are better suited to real-world clinical scenarios—therapies that are potent, precise, and adaptable to advanced stages of IRDs in both human and veterinary applications.

A provisional patent on the promoter technology has been filed by the University of Pennsylvania, signaling the potential for commercial development and future clinical application.

Reference:

Raghavi Sudharsan et al, Novel Photoreceptor-Specific Promoters for Gene Therapy in Mid-to-Late Stage Retinal Degeneration, Molecular Therapy (2025). DOI: 10.1016/j.ymthe.2025.05.020