Applied Genetic Technologies Corporation (AGTC), announced that it has identified Stargardt disease as the second ophthalmology program in its previously announced preclinical pipeline expansion, which also includes a program targeting the dry form of age-related macular degeneration (AMD). The company is also reporting proof-of-concept expression data for its Stargardt disease gene therapy candidate in non-human primates (NHPs).
Stargardt disease, the most common form of inherited macular degeneration, occurs in 1 in 8,000-10,000 individuals and most often results from mutations in the ABCA4 gene. Loss of functional ABCA4 protein leads to the accumulation of toxic substances in photoreceptors, resulting in photoreceptor death and progressive vision loss. A key challenge in developing an AAV-based gene therapy for the treatment of Stargardt disease is that the DNA sequence encoding the ABCA4 protein exceeds the payload capacity of AAV vectors. AGTC’s Stargardt disease program effectively addresses this challenge by dividing the coding sequence into two separate AAV vectors. Once inside the cell, the two DNA fragments recombine to form the complete coding sequence, which produces full length, functional ABCA4 protein.
“The expansion of our preclinical pipeline to include Stargardt disease and dry AMD demonstrates the broad therapeutic and commercial utility of our proprietary AAV gene delivery platform,” Sue Washer, President and CEO of AGTC, said in a company news release. “Our Stargardt disease program underscores our ability to leverage our expertise in AAV vector and genome engineering to expand AAV gene therapy into new indications that require delivery of larger DNA payloads. Dry AMD represents a compellingly large market opportunity given that the disease affects over 24 million people globally. Each of these preclinical programs builds on our industry-leading capabilities in gene therapy for retinal diseases and will leverage our expanding expertise in designing and implementing preclinical and clinical studies that are optimized for success.”
William Hauswirth, PhD, a leading innovator in AAV gene therapy at the University of Florida and a long-term academic collaborator with AGTC, and his colleagues at the University of British Columbia, recently published data demonstrating that a hybrid ABCA4 dual AAV vector system was safe and provided therapeutic benefit in a mouse model of Stargardt disease.1 Researchers at AGTC optimized the vectors used in Dr. Hauswirth’s study for administration to NHPs. In a 13-week study, subretinal injection of AAVs prepared at AGTC encoding the N-terminal fragment and C-terminal fragment of human ABCA4, which was tagged to distinguish it from the naturally occurring non-human primate ABCA4 protein, resulted in clear detection of full length recombinant human ABCA4 protein. The protein was detected in tissue punches harvested from inside the subretinal bleb, but not in the untreated surrounding tissue, confirming the specificity and effectiveness of the vector administration. These results in NHPs are an important technical advance for the use of dual AAV vector expression systems in retinal gene therapy. Based on the results of this study, AGTC is continuing therapeutic development of its optimized dual vector system for the treatment of Stargardt disease.
“Our recent publication provided important proof-of-concept data supporting the safety and therapeutic utility of using a dual AAV vector system to deliver and express the ABCA4 protein,” William W. Hauswirth, PhD, Professor of Ophthalmology and the Maida and Morris Rybaczki Eminent Scholar Chair in Ophthalmic Sciences in the Department of Ophthalmology at the University of Florida, said in a company news release. “AGTC’s demonstration that this approach is safe and results in ABCA4 protein expression in NHPs following subretinal injection of their optimized vectors is an important milestone in advancing gene therapy for Stargardt disease toward the clinic.”
1 Dyka FM, Molday LL, Chiodo VA, Molday RS and Hauswirth WW. Dual ABCA4-AAV vector treatment reduces pathogenic retinal A2E accumulation in a mouse model of autosomal recessive Stargardt disease. Hum Gene Ther. 2019 Sep 30. doi: 10.1089/hum.2019.132.