Recombinant Adeno-Associated Virus as a Delivery Platform for Ocular Gene Therapy: A Comprehensive Review

Jiang-Hui Wang; Wei Zhan; Thomas L Gallagher; Guangping Gao

doi:10.1016/j.ymthe.2024.10.017

Recombinant Adeno-Associated Virus as a Delivery Platform for Ocular Gene Therapy: A Comprehensive Review

Mol Ther. 2024 Oct 25:S1525-0016(24)00677-4. doi: 10.1016/j.ymthe.2024.10.017. Online ahead of print.

Authors

Jiang-Hui Wang¹, Wei Zhan², Thomas L Gallagher³, Guangping Gao⁴

Affiliations

¹ Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC 3002, Australia.
² Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁴ Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].

PMID: 39489915
DOI: 10.1016/j.ymthe.2024.10.017

Abstract

Adeno-associated virus (AAV) has emerged as a leading platform for in vivo gene therapy, particularly in ocular diseases. AAV-based therapies are characterized by low pathogenicity and broad tissue tropism and have demonstrated clinical success as exemplified by Luxturna being the first gene therapy to be approved by the U.S. Food and Drug Administration to treat RPE65-associated Leber congenital amaurosis (LCA). However, several challenges remain in the development of AAV-based gene therapies, including immune responses, limited cargo capacity, and the need for enhanced transduction efficiency, especially for intravitreal delivery to photoreceptors and retinal pigment epithelium (RPE) cells. This review explores the biology of AAVs in the context of gene therapy, innovations in capsid engineering, and clinical advancements in AAV-based ocular gene therapy. We highlight ongoing clinical trials targeting inherited retinal diseases and acquired conditions, discuss immune-related limitations, and examine novel strategies for enhancing AAV vector performance to address current barriers.

Publication types

Review