Key result
Pre-existing anti-AAV antibodies pose a significant hurdle to AAV gene therapy, but emerging strategies like IgG-cleaving proteases (IdeS/IdeZ) and plasmapheresis offer promising solutions.
Why the study?
Increasing use of AAV vectors creates an urgent need to establish protocols for determining therapeutically relevant titers of pre-existing anti-AAV antibodies and strategies to deplete them.
This review highlights the challenges posed by pre-existing anti-AAV antibodies in gene therapy and discusses potential solutions such as plasmapheresis and IgG-cleaving proteases.
Anti-AAV antibodies limit AAV gene therapy access; leaves open whether IgG-cleaving proteases or plasmapheresis will enable broader use.
gene therapy approved in the US and Europe. The recent tragic death of three children in a clinical trial to treat X-Linked Myotubular Myopathy by delivering myotubularin with an AAV8 vector notwithstanding, AAV remains a highly promising therapeutic gene delivery platform. But the successful use of AAV vectors to treat an increasing number of diseases also makes establishing protocols to determine therapeutically relevant titers of pre-existing anti-AAV antibodies and approaches to deplete those antibodies more urgent than ever. In this mini review, I will briefly discuss (i) our knowledge regarding the prevalence of anti-AAV antibodies, (ii) the challenges to measure those antibodies by methods that are most predictive of their influence on therapeutic efficacy of AAV gene transfer, and (iii) approaches to overcome the formidable hurdle that anti-AAV antibodies pose to the successful clinical use of AAV gene therapy.
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Thomas Weber (2021) conducted a review in Genetic diseases requiring AAV gene therapy. AAV gene therapy and anti-AAV antibody mitigation strategies was evaluated. Pre-existing anti-AAV antibodies pose a significant hurdle to AAV gene therapy, but emerging strategies like IgG-cleaving proteases (IdeS/IdeZ) and plasmapheresis offer promising solutions.
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