Penn Vet Gene Therapy Study Advances Another Potential Treatment for Rare Inherited Blinding Disease into Human Clinical Trial

Vision scientists at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) and the Center for Hereditary Retinal Degenerations at the Perelman School of Medicine have taken an important step toward a new treatment for Best vitelliform macular dystrophy, commonly called Best disease, a rare juvenile-onset dominant eye disorder that gradually robs people of their vision. Best disease is an inherited disorder caused by mutations in the BEST1 gene, and there is no cure. The disease damages the macula, the central portion of the retina responsible for the sharp vision needed for reading, driving, and recognizing faces.

In a study published in Human Gene Therapy, the investigators demonstrated that a gene therapy restored retinal structure and function in dogs with naturally-occurring mutations in the BEST1 gene, the same gene responsible for Best disease and related inherited retinal disorders in people, such as autosomal recessive bestrophinopathy (ARB). The findings provided the critical preclinical evidence needed to support an Investigational New Drug (IND) application submitted to the U.S. Food and Drug Administration (FDA) to conduct early-stage human clinical trials (Phase 1b/2a) of the therapy in individuals living with these conditions. Opus Genetics Inc. has now launched these studies and recently announced that it has completed enrollment of the first cohort of participants, a mix of patients with the dominant and recessive forms of BEST1 retinal disease.

“Nature gave us an extraordinary partner in these dogs,” said William Beltran, DVM, PhD, DECVO, Corinne R. and Henry Bower Professor of Ophthalmology and director of the Division of Experimental Retinal Therapies. “Because they naturally develop the same inherited retinal disease seen in people, they allowed us to evaluate this therapy in ways that no other animal or alternative method can. What we learned from them directly shaped the treatment now being administered in human patients.”

The therapy, known as OPGx-BEST1, delivers a healthy copy of the BEST1 gene directly to retinal cells. Researchers evaluated the treatment in dogs with naturally occurring BEST1 mutations, monitoring them for more than three months to determine whether the therapy was both safe and effective.

The results were encouraging.

Investigators found no significant safety concerns. Routine health evaluations, detailed eye examinations, and microscopic analysis of retinal tissue showed no evidence that the therapy damaged the eye or other organs.

More importantly, treated retinas became healthier.

Advanced imaging showed that disease lesions shrank or disappeared in treated areas, while untreated regions continued to show signs of disease progression. Microscopic examination also confirmed the preservation of the light-sensing photoreceptor cells, which often deteriorate as the disease advances.

The therapy also improved retinal function. Electroretinography, which measures the retina’s electrical response to light, showed significantly stronger rod- and cone-mediated responses in treated eyes than in untreated eyes, indicating that the therapy not only improved retinal structure but also visual function.

Together, the findings established that the therapy could be delivered safely while preserving and improving retinal function, critical pieces of information required for the IND submission to the FDA.

The study is based on the work by Beltran and Gustavo D. Aguirre, VMD, PhD, professor of Medical Genetics and Ophthalmology, and their long-term collaborators Artur Cideciyan and the late Samuel Jacobson, both experts on inherited retinal degenerations, including Bestrophinopathies, at Penn’s Scheie Eye Institute. Aguirre’s internationally renowned research, spanning nearly five decades, has investigated the genetic basis of a variety of inherited vision disorders in dogs, including congenital blindness, retinitis pigmentosa, achromatopsia (day blindness), and Best disease. This seminal work has provided clinically relevant animal models demonstrating that novel gene therapy approaches that deliver a functional copy of a defective gene to the eye can halt vision loss or even restore sight. The therapy for a form of Leber’s congenital amaurosis caused by mutations in the RPE65 gene is now commercialized after successful completion of studies in dogs and human clinical trials.

“The goal of our work is to identify the genetic causes of blindness and to cure blindness through gene therapies and other approaches,” said Aguirre. “With BEST1 gene therapy now in clinical trials, this is the fourth program that the Division of Experimental Retinal Therapies has successfully moved to human patients.”

Corresponding author William A. Beltran is a professor in the Department of Clinical Sciences and Advanced Medicine.

Gray et al. study: Alexa Gray, Jennifer Kwok, Yu Sato, Charles-Antoine Assenmacher, Gustavo D. Aguirre, and William A. Beltran, Penn Vet; Hua Peiying, Gui-Shuang Ying, Malgorzata Swider, Alexander Sumaroka, and Artur Cideciyan, Scheie Eye Institute, Perelman School of Medicine; and Mayur Choudhary and Ash Jayagopal, Opus Genetics, Inc.

The work was supported by the National Institutes of Health/National Eye Institute, the Foundation Fighting Blindness, Iveric Bio Inc., and Opus Genetics Inc.

This news release was drafted with the assistance of Claude Sonnet 4.6, an advanced AI language model, modified and approved by the study’s authors.