Adeno-associated virus as a delivery vector for gene therapy of human diseases

Abstract

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.

Characterizing Glycosylation of Adeno-Associated Virus Serotype 9 Capsid Proteins Generated from HEK293 Cells through Glycopeptide Mapping and Released Glycan Analysis

“…The three viral proteins share a common C-terminus and are present in one AAV at an approximate 1:1:10 ratio [3,4]. AAV vectors, with their nonpathogenic nature and the ability to provide long-term gene expression, have emerged as prominent gene delivery vehicles to treat a number of human diseases [5,6]. AAV capsid proteins determine tissue specificity and immunogenicity and play important roles in receptor binding, the escape of the virus from the endosome, and the transport of viral DNA to the nuclei of target cells.…”

Transcriptomics-informed pharmacology identifies epigenetic and cell cycle regulators as enhancers of AAV production

“…Recombinant AAVs (rAAVs) have gained popularity in the gene therapy field due to their well-established safety profile, broad and tunable tropism and nonpathogenic nature (Pupo et al, 2022; Samulski and Muzyczka, 2014). As of 2024, we have seven commercially approved rAAV gene therapies (FDA, 2024), several programs in late stage clinical development, and hundreds in earlier stages of development (Kuzmin et al, 2021; Wang et al, 2024).…”

A Drug-Elicitable Alternative-Splicing Module (DreAM) for Tunable AAV Expression and Controlled Myocardial Regeneration

“…Proper selection of tissue-specific promoters and AAV capsids could achieve targeted AAV gene expression in these organs 2 . AAV gene expression could last for years, which is suitable for gene supplementation therapy 3 . However, AAV lacks the ability to flexibly adjust the duration and level of transgene expression, which profoundly restricts their applicable indications and raises additional concerns about efficacy and safety, especially in scenarios when transient or fluctuated gene expression is more desirable.…”