Gene therapy cures canines of inherited form of day blindness

Achromatopsia is a rare autosomal recessive disorder with an estimated prevalence in human beings of about 1 in 30,000 to 50,000. It primarily affects the function of the cone photoreceptors in the retina and serves as a representative model for other more common inherited retinal disorders affecting cones. Cone function is essential for color vision, central visual acuity and most daily visual activities, which underlines the importance of the newly developed treatment.

The treatment cured younger canines regardless of the mutation that caused their achromatopsia. It was effective for the 33 months of the study and most likely is permanent; however, researchers also observed a reproducible reduction in the cone therapy success rate in dogs treated at 54 weeks of age or older.

The successful therapy in dogs was documented by the restoration of the cone function using electroretinography and by objective measure of day vision behavior. The behavioral results suggest that inner retinal cells and central visual pathways were able to usefully process the input from the recovered cones.

The results represent the second successful cone-directed gene replacement therapy in achromatopsia animal models and the first outside of mouse models. The gene therapy targets mutations of the CNGB3 gene, the most common cause of achromatopsia in humans. Achromatopsia-affected dogs represent the only natural large animal model of CNGB3-achromatopsia.

The results hold promise for future clinical trials of cone-directed gene therapy in achromatopsia and other cone-specific disorders.

"The successful restoration of visual function with recombinant adeno-associated virus-mediated gene replacement therapy has ushered in a new era of retinal therapeutics," said András M. Komáromy, assistant professor of ophthalmology at the Penn School of Veterinary Medicine and lead author of the study.

Many vision-impairing disorders in humans result from genetic defects, and, to date, mutations have been identified in ~150 genes out of ~200 mapped retinal disease loci. This wealth of genetic information has provided fundamental understanding of the multiple and specialized roles played by photoreceptors and the retinal pigment epithelium in the visual process and how mutations in these genes result in disease. Together with the development of gene-transfer technologies, it is now possible to realistically consider the use of gene therapy to treat these previously untreatable disorders.

The article, available online in advance of its publication in the journal Human Molecular Genetics, was conducted by Komáromy, Jessica S. Rowlan and Gustavo D. Aguirre of the Department of Clinical Studies at Penn Vet; Monique M. Garcia, Asli Kaya and Jacqueline C. Tanaka of Temple University; John J. Alexander of the University of Florida and the University of Alabama; Vince A. Chiodo and William W. Hauswirth of the University of Florida; and Gregory M. Acland of Cornell University.

Research was supported by the National Eye Institute of the National Institutes of Health, the Foundation Fighting Blindness, the Macula Vision Research Foundation, the McCabe Fund, the ONCE International Prize, the Van Sloun Fund for Canine Genetic Research, Hope for Vision and Brittany Rockefeller and family.

Hauswirth and the University of Florida have a financial interest in the use of rAAV therapies and own equity in Applied Genetic Technologies Corp., a company that may commercialize some aspects of this work. The University of Pennsylvania, the University of Florida and Cornell University hold a patent on the described gene-therapy technology.