{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:29:30Z","timestamp":1791325770252,"version":"4.3.1"},"reference-count":160,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009663","name":"University Health Network","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>\n                    There is great anticipation that gene therapies can offer solutions to many neurological diseases. Already, much is known about therapeutic targets and how they would need to be manipulated to mitigate disease. For such gene therapies to move to the clinic, potent CNS delivery vehicles are needed. One line of investigation focuses on adeno-associated viruses (AAV) to address this need. In particular, blood\u2013brain barrier (BBB)-penetrant AAV capsids are of interest due to the relative ease of their intravenous administration. This review will introduce this topic and provide an update on recent developments. First, we describe the physical barriers that must be overcome for AAV-delivered gene therapies to reach target cells in the CNS. We then put a spotlight on the natural AAV9 capsid\u2019s inherent propensity to cross the BBB and key lessons learned from its use for delivering a therapeutic payload for the treatment of spinal muscular atrophy. Next, we summarize methods for engineering recombinant AAV (rAAV) capsids with improved brain penetrance, and present\n                    <jats:italic>in vitro<\/jats:italic>\n                    paradigms for predicting their capacity to cross the human BBB. We also present strategies for side-stepping the delivery limitations of existing rAAV vectors. Finally, we point toward a few notable clinical studies whose outcomes may advance our understanding of what rAAV-delivered gene therapies can offer to people afflicted with CNS disorders.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1768545","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:55:01Z","timestamp":1772088901000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases"],"prefix":"10.3389","volume":"20","author":[{"given":"Alissa","family":"Pak","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darcy","family":"Wear","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nareh","family":"Tahmasian","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Yeon","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davina","family":"Premraj","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiah","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zerbes","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]},{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medha","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]},{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Nasser","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]},{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerold","family":"Schmitt-Ulms","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto","place":["Toronto, ON, Canada"]},{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/j.cell.2016.11.048","article-title":"A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response","volume":"167","author":"Adamson","year":"2016","journal-title":"Cell"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3390\/genes13020248","article-title":"Mucolipidosis type IV in Omani families with a novel MCOLN1 mutation: search 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