Toward improved AAV gene therapies for retinal disorders: challenges and advances

Abstract

Adeno-associated virus (AAV) vectors have transformed the landscape of in vivo gene therapy, with retinal diseases emerging as a major area of progress. The eye offers unique advantages as a therapeutic target: it is accessible, compartmentalized, and relatively immune-privileged, allowing localized delivery with reduced systemic effects. The landmark 2017 approval of the first AAV-based gene therapy for an inherited retinal disorder sparked a surge of clinical trials using AAV vectors - underscoring their potential for treating genetic eye diseases. However, challenges remain, including AAV's limited capacity for large genes, suboptimal precision in cell-type-specific targeting, and inefficient transduction of certain retinal cells via minimally invasive routes. In response, researchers are engineering next-generation AAV capsids, optimizing gene expression cassettes, developing novel delivery strategies, and advancing tissue and organoid-based screening platforms. This article highlights these efforts as essential to overcoming current barriers in retinal AAV gene therapy.

Keywords: Retinal disorder; adeno-associated virus; gene therapy; organoids; vector design; virus delivery.