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 a multidisciplinary project to test a new retinal adhesive thermoresponsive gel for delivering an adeno-associated virus (AAV)-mediated gene therapy to the outer retina for treating Leber Congenital Amaurosis (variant NPHP5-LCA). This ambitious project is funded by two complementary grants, one a National Institutes of Health R01 award and the other a grant from the U.S. Department of Defense (DOD) Military Operational Medicine Research Program (MOMRP).
Research Team
The research team from the UPMC Vision Institute includes department chair, José-Alain Sahel, MD; along with co-principal investigators Leah Byrne, PhD; and Morgan DiLeo, PhD. Also a co-investigator on the NIH R01 portion of the project is William Beltran, DVM, MSc, PhD, DECVO, professor of Ophthalmology at the University of Pennsylvania School of Veterinary Medicine.
Contributing to the DOD MOMRP award project is co-investigator Valentina Emiliani, PhD, from the Institut de la Vision in Paris, France.
Collaborating on the study’s surgical components from the UPMC Vision Institute are Joseph Martel, MD, and ophthalmology postdoctoral fellow Anfisa Ayalon, MD.
Background
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 coupled with optogenetics 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 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 Details
The research 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 AAV gene therapy directly onto the retina. This precision targeting 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 hope is that this new approach will reduce the immune reactions often triggered by traditional intravitreal injection of gene therapy treatment. Additionally, it might decrease the treatment dosage required.
To verify their approach, the team will test the gel on a preclinical animal model of Leber Congenital Amaurosis. Dr. Beltran’s expertise in these preclinical models is a critical component of progressing this treatment method toward the clinic.
The DOD-funded portion of the project layers in an optogenetic component to the research that will allow the investigators to enable optical modulation of target cells in the retina that closely mirrors the stimulation pattern occurring in a healthy retina. This aspect of the research leverages Dr. Emiliani’s expertise in computer-generated holography and stimulation modeling.
Looking Ahead
Combining the thermogel delivery system for the AAV-mediated gene therapy with an optogenetic component 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, the approach being tested by the research team could potentially reshape the treatment approach for multiple retinal disorders and other conditions that affect the eye.
References and Further Reading
