Understanding AAV vector immunogenicity: from particle to patient

Abstract

Gene therapy holds promise for patients with inherited monogenic disorders, cancer, and rare genetic diseases. Naturally occurring adeno-associated virus (AAV) offers a well-suited vehicle for clinical gene transfer due to its lack of significant clinical pathogenicity and amenability to be engineered to deliver therapeutic transgenes in a variety of cell types for long-term sustained expression. AAV has been bioengineered to produce recombinant AAV (rAAV) vectors for many gene therapies that are approved or in late-stage development. However, ongoing challenges hamper wider use of rAAV vector-mediated therapies. These include immunity against rAAV vectors, limited transgene packaging capacity, sub-optimal tissue transduction, potential risks of insertional mutagenesis and vector shedding. This review focuses on aspects of immunity against rAAV, mediated by anti-AAV neutralizing antibodies (NAbs) arising after natural exposure to AAVs or after rAAV vector administration. We provide an in-depth analysis of factors determining AAV seroprevalence and examine clinical approaches to managing anti-AAV NAbs pre- and post-vector administration. Methodologies used to quantify anti-AAV NAb levels and strategies to overcome pre-existing AAV immunity are also discussed. The broad adoption of rAAV vector-mediated gene therapies will require wider clinical appreciation of their current limitations and further research to mitigate their impact.

Delivery of DNA-Based Therapeutics for Treatment of Chronic Diseases

“…Since AAVs are endemic and non-pathogenic [ 19 ], many individuals do not realize they have been exposed to AAVs. Globally, studies have seen the highest level of serotype positivity (seroprevalence or seropositivity) being associated with AAV2, and lowest associated with AAV5 [ 36 , 37 ]. Exposure to AAVs can correlate with pre-existing immunity to various serotypes, limiting success of treatments [ 36 , 38 , 39 ].…”

“…Globally, studies have seen the highest level of serotype positivity (seroprevalence or seropositivity) being associated with AAV2, and lowest associated with AAV5 [ 36 , 37 ]. Exposure to AAVs can correlate with pre-existing immunity to various serotypes, limiting success of treatments [ 36 , 38 , 39 ]. Testing for pre-existing antibodies against AAVs has been introduced as a strategy to determine treatment eligibility to avoid such issues [ 38 , 39 , 40 ].…”

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression

“…This CSL Behring gene therapy product, originally developed by UniQure, was approved by the FDA in 2022 based on safety and efficacy studies in adult male patients with severe or moderately severe disease. 49 , 50 Roctavian is an AAV5 vector-based gene therapy for the treatment of patients with severe hemophilia A who do not have a history of coagulation factor VIII inhibitors or detectable antibodies to the AAV5 type. On August 24, 2022, this therapy was conditionally approved by the European Medicines Agency, and on June 29, 2023, it was approved by the US FDA.…”