The evolution of adeno-associated virus capsids for CNS gene therapy

Adeno-associated virus (AAV) is emerging as a dominant gene therapy delivery vehicle, and the broad tool kit of naturally-occurring AAV capsid variants has allowed tailoring of approaches for specific applications. For example, Glybera^® (AAV1) is targeted to muscle, Luxterna™ (AAV2) is targeted to the retina, and Zolgensma^® (AAV9) is targeted to the central nervous system (CNS). In the context of CNS gene therapy, the discovery of AAV9 was largely responsible for a shift from direct intraparenchymal brain injections to approaches that more globally target the brain, such as intravenous injection and/or injection into the cerebrospinal fluid (CSF). In fact, one could divide CNS gene therapy into ‘pre-AAV9’ and ‘post-AAV9’ eras, due to the dramatic leap that this vector technology enabled. One can envision a similar future leap coming, as lab-derived improvements to capsids are being made that could further increase the efficiency and specificity of CNS-directed gene therapy. Recent advancements in AAV vectors are discussed.

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