Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis

• DOI: 10.1093/hmg/ddr391
• Publication Date: 2011-09-01T10:58:44Z
• Authors: Cristy A. Ku; Vince A. Chiodo; Sanford L. Boye; Andrew F.X. Goldberg; Tiansen Li; William W. Hauswirth; Visvanathan Ramam...
• Keywords: Adeno-associated virus

Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects characterized at most severe end of LCA spectrum. The rapid photoreceptor loss observed patient population mimicked mouse model lacking AIPL1. Using this model, we evaluated if replacement therapy using recent advancements adeno-associated viral vectors (AAV) provides advantages preventing degeneration. Specifically, demonstrated that novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) provided greater preservation photoreceptors functional null mice compared single-stranded AAV2/8. benefits sc-Y733F-AAV were evident following administration during active phase degeneration, where only treatment achieved rescue. This result was likely due to higher earlier onset expression. Based on our studies, conclude sc-Y733F-AAV2/8 vector, date, achieves best rescue for mice. Our results provide important considerations be used future clinical trials targeting wider severity spectrum inherited dystrophies.