Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.
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The authors thank their colleagues at Voyager Therapeutics for numerous discussions on adeno-associated viral (AAV) gene therapy for central nervous system (CNS) disorders and the Parkinson disease team and P. Larson for their work on the delivery of AAV2–aromatic-L-amino-acid decarboxylase (AADC) gene therapy in patients with Parkinson disease with intraparenchymal brain administration. The authors also thank E. Smith, W. Yen and M. Lawrence for assistance with the figures, tables and text, respectively. B.E.D. was supported by the Beckman Institute for the CLARITY, Optogenetics and Vector Engineering Research Center (CLOVER) at the California Institute of Technology, the Friedreich's Ataxia Research Alliance (FARA) and FARA Australasia and the CHDI Foundation and is currently supported by the Stanley Center for Psychiatric Research at Broad Institute. K.S.B. was supported by the Michael J. Fox Foundation. B.M.R., S.M.P. and D.W.Y.S. are currently employees of Voyager Therapeutics, a CNS gene therapy company working on AAV vectors for the treatment of severe neurological diseases.
The authors declare competing financial interests in the form of funding from Voyager Therapeutics, employment by Voyager Therapeutics and/or personal financial interests in Voyager Therapeutics.
The protein shell of the virus that protects the adeno-associated viral genome and mediates entry into and trafficking within the host cell.
(IPa). Direct delivery of an agent into the tissue of interest.
(IT). A route of access into the spinal cord cerebrospinal fluid via the space under the arachnoid membrane.
(ICV). A route of access into the CSF via the cerebral ventricles (typically the lateral ventricle).
Specificity for a particular host tissue or cell type.
Capsid variants or groups of capsids that have distinct neutralization properties.
A route of access into the CSF via the cerebellomedullary cistern.
Genus of parvoviruses that are replication-incompetent in the absence of co-infection of the host cell with a second virus such as an adenovirus or HSV.
- Self-complementary AAV
An AAV genome that has been modified by elimination of the 5′ terminal resolution site and can fold into double-stranded DNA without the requirement for DNA synthesis.
- Convection enhanced delivery
(CED). Infusion of adeno-associated viral vectors or other molecules into the parenchyma under positive pressure to increase the distribution volume.
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Deverman, B., Ravina, B., Bankiewicz, K. et al. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov 17, 641–659 (2018). https://doi.org/10.1038/nrd.2018.110
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