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Adeno-associated virus vectors and neurotoxicity—lessons from preclinical and human studies

Abstract

Over 15 years after hepatotoxicity was first observed following administration of an adeno-associated virus (AAV) vector during a hemophilia B clinical trial, recent reports of treatment-associated neurotoxicity in animals and humans have brought the potential impact of AAV-associated toxicity back to prominence. In both pre-clinical studies and clinical trials, systemic AAV administration has been associated with neurotoxicity in peripheral nerve ganglia and spinal cord. Neurological signs have also been seen following direct AAV injection into the brain, both in non-human primates and in a clinical trial for late infantile Batten disease. Neurotoxic events appear variable across species, and preclinical animal studies do not fully predict clinical observations. Accumulating data suggest that AAV-associated neurotoxicity may be underdiagnosed and may differ between species in terms of frequency and/or severity. In this review, we discuss the different animal models that have been used to demonstrate AAV-associated neurotoxicity, its potential causes and consequences, and potential approaches to blunt AAV-associated neurotoxicity.

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Fig. 1: AAV delivery routes into the nervous system.

Data availability

No datasets were generated for this review. All works reviewed in this study are referenced in the published article.

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Acknowledgements

We thank the members of the Jerome lab for thoughtful discussions.

Funding

Research in our laboratory is funded by NIH grants R21AI117519, R01AI132599, UM1 AI126623, amfAR, the Caladan Foundation, over 1600 individual donors, and, in part, by a developmental grant from the University of Washington Center for AIDS Research (CFAR), an NIH-funded program under award number P30 AI 027757, which is supported by the following NIH Institutes and Centers (NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, and NIDDK), and in part by NIH/NCI Cancer Center Support Grant P30 CA015704.

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DS, MA, and KRJ conceived and wrote the paper.

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Correspondence to Daniel Stone, Martine Aubert or Keith R. Jerome.

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KRJ is a paid advisor and holds equity in Excision Biosciences, has sponsored research agreements with Excision Biosciences and Emendo Biotherapeutics, and is co-inventor of patents held by Fred Hutch regarding AAV-delivered gene therapy. DS and MA have sponsored research agreements with Excision Biosciences.

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Stone, D., Aubert, M. & Jerome, K.R. Adeno-associated virus vectors and neurotoxicity—lessons from preclinical and human studies. Gene Ther (2023). https://doi.org/10.1038/s41434-023-00405-1

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