Gene therapy is making a comeback. With its twin promise of targeting disease etiology and ‘long-term correction’, gene-based therapies (defined here as all forms of genome manipulation) are particularly appealing for neurodegenerative diseases, for which conventional pharmacologic approaches have been largely disappointing. The recent success of a viral-vector-based gene therapy in spinal muscular atrophy—promoting survival and motor function with a single intravenous injection—offers a paradigm for such therapeutic intervention and a platform to build on. Although challenges remain, the newfound optimism largely stems from advances in the development of viral vectors that can diffusely deliver genes throughout the CNS, as well as genome-engineering tools that can manipulate disease pathways in ways that were previously impossible. Surely spinal muscular atrophy cannot be the only neurodegenerative disease amenable to gene therapy, and one can imagine a future in which the toolkit of a clinician will include gene-based therapeutics. The goal of this Review is to highlight advances in the development and application of gene-based therapies for neurodegenerative diseases and offer a prospective look into this emerging arena.
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The authors thank L. Parra, B. Aulston, D. Galasko, and J. Brewer (all at UCSD) for comments on the manuscript. The authors apologize that due to space restrictions, primary papers could not be cited in most cases. Work in the Sun Lab is supported by NSFC grants 82071193 and 32000673. Work in the Roy Lab is supported by grants from the NIH (R01AG048218, R01NS11978, R01NS075233, R21AG052404 and UG3NS111688) and the US–Israel Binational Science Foundation (BSF, number 2019248).
J.S. and S.R. have applied for patents related to gene editing in AD (US patent application number 16251970). S.R. is also the scientific founder of, advisor to, and owns equity in CRISPRAlz.
Peer review information Nature Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.
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Sun, J., Roy, S. Gene-based therapies for neurodegenerative diseases. Nat Neurosci 24, 297–311 (2021). https://doi.org/10.1038/s41593-020-00778-1