Adeno-associated virus as a delivery vector for gene therapy of human diseases
- Signal Transduct Target Ther. 2024 Apr 3;9(1):78. doi: 10.1038/s41392-024-01780-w.
- 1. Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- 2. Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- 3. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, 3002, Australia.
- 4. Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, 3002, Australia.
- 5. Department of Neurological Surgery, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- 6. Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA.
- 7. Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- 8. Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- 9. Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. [email protected].
- 10. Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. [email protected].
- 11. Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. [email protected].
- # Contributed equally.
Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, Hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.