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R01 Awarded to UPMC Vision Institute/Pitt Ophthalmology Research Team to Develop and Test New Thermoresponsive Gel for Delivery of Retinal AAV Gene Therapy

April 17, 2024

A research team from the UPMC Vision Institute is at work on project funded by the National Institutes of Health R01 and the Department of Defense to test a new retinal adhesive thermoresponsive gel for delivering an AAV-mediated gene therapy to the outer retina for treating two variants of Leber Congenital Amaurosis (NPHP5-LCA, and RPE65-LCA2 variants, respectively).


Retinal pathologies have long posed diagnostic and therapeutic challenges for ophthalmologists. Genetically driven retinal degeneration diseases are characterized by the progressive loss of photoreceptors or other retinal cellular constituents, leading to progressive vision impairment or blindness. Many of these conditions are inherited and can be traced to mutations in specific genes. As our understanding of the genetic bases of these disorders has progressed, gene-based therapeutics have emerged as highly promising avenues for targeted treatments.

When the U. S. Food and Drug Administration approved the gene therapy Luxturna for retinal dystrophies linked to specific RPE65 mutations, it signaled the beginning of new era for gene-based treatments. However, given the broad spectrum of genetically driven retinal conditions, there remains a clear need for innovative therapies that address a broader range of these diseases.

There also exists the need to devise innovative, efficacious, and safe patient-centric methods for delivering targeted gene-based therapies to treat disease of the retina and the broader constellation of genetically driven ocular diseases.

And that’s exactly what the new project is designed to do.

Research Team

The research team consists of department chair, José-Alain Sahel, MD; Leah Byrne, PhD; and Morgan DiLeo, PhD. Also a co-investigator on the NIH grant is William Beltran, DVM, MSc, PhD, DECVO, professor of Ophthalmology at the University of Pennsylvania School of Veterinary Medicine. The DOD-funded award, which adds an optogenetic component to enable optical modulation of select cells, includes co-investigator Valentina Emiliani, PhD, from the Institut de la Vision in Paris, France.

Grant Highlights

The team, under the direction of Dr. Sahel, has designed a specialized gel that can deliver an AAV-mediated gene therapy. Instead of the usual systemic delivery via topical application, this gel deposits the AAVs directly onto the retina. This precision not only ensures that the treatment reaches its intended location, but also minimizes the chances of complications that could arise from less direct methods.

Furthermore, the team plans to enhance the gel with an added backing layer developed by Dr. DiLeo’s biomaterials laboratory. This layer is designed to provide a greater degree of control over the release of the therapeutic vectors. By giving directionality to the vector release, it can improve delivery while also optimizing it for superior outcomes. The team is also poised to improve the transfection efficacy and specificity of the viral vectors using Dr. Byrne’s custom engineered vectors and promoters. The team is hope that this new approach will reduce the immune reactions often triggered by traditional intravitreal injection of gene therapy treatment. Additionally, it might decrease the amount of treatment dosage required.

To verify their approach, the team will test the gel on two canine models of Leber Congenital Amaurosis (LCA): NPHP5-LCA and RPE65-LCA2. Dr. Beltran’s expertise in these preclinical models is a critical component of progressing this treatment method toward the clinic. In the DOD portion, stimulation of specific cells will be optimized using Dr. Emiliani’s expertise in computer generated holography and stimulation modeling.

Looking Ahead

The gel platform being developed by Dr. Sahel’s team may eventually be applicable to a variety of outer retinal conditions amenable to gene-based therapy. By offering a method for direct and efficient AAV delivery, this platform could potentially reshape the treatment approach for multiple retinal disorders and other conditions that affect the eye.