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Published October 2021 | Published + Supplemental Material
Journal Article Open

Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice


Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1^(m1N/m1N) mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1^(m1N/m1N) mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1^(m1N/m1N) mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

Additional Information

© 2021 Davidson et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). Received January 28, 2021. Revision received August 4, 2021. Accepted August 4, 2021. Published online 18 August 2021. We are grateful for the wealth of expertise and technical assistance regarding droplet digital PCR provided by Valery Bliskovsky, Steven Shema, and Liz Conner in the National Cancer Institute's Genomics Core. The dedicated National Institutes of Health (NIH) animal care and veterinary staff is gratefully acknowledged for their commitment to the care and well-being of all animals in our facilities, especially the mice included in this study. Finally, and perhaps most importantly, the unwavering support and trust in research by NPC-affected patients and families is a powerful reminder of why our collective efforts as a research community must prevail. This research was funded by the Intramural Research Program of the National Human Genome Research Institute (NHGRI) at the NIH (1ZIAHG000068-15). Additional support was generously provided by Liferay, Inc. (Postbaccalaureate Intramural Research Training Award for AL Gibson) and Niemann-Pick Canada and Ara Parseghian Medical Research Fund at the University of Notre Dame. Support for CD Davidson was kindly provided by the Hide & Seek Foundation and Dana's Angels Research Trust (both part of Support Of Accelerated Research for Niemann-Pick C). Work performed at the California Institute of Technology was supported by NIH Pioneer grant (DP1OD025535; V Gradinaru) and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER) for technology development and dissemination (V Gradinaru). JL Rodriguez-Gil was supported by an NHGRI Intramural Research Training Award, the NIH Oxford-Cambridge Scholars Program, and the Medical Scientist Training Program from the School of Medicine and Public Health, University of Wisconsin-Madison (3T32GM008692). Author Contributions: CD Davidson: conceptualization, formal analysis, investigation, visualization, project administration, and writing—original draft, review, and editing. AL Gibson: investigation and writing—original draft, review, and editing. T Gu: investigation and writing—original draft, review, and editing. LL Baxter: formal analysis, visualization, and writing—original draft, review, and editing. BE Deverman: conceptualization, resources, investigation, and writing—review and editing. K Beadle: investigation and writing—review and editing. AA Incao: investigation and writing—review and editing. JL Rodriguez-Gil: formal analysis, investigation, and writing—review and editing. H Fujiwara: formal analysis and writing—review and editing. X Jiang: formal analysis, investigation, and writing—review and editing. RJ Chandler: conceptualization and writing—review and editing. DS Ory: resources and writing—review and editing. V Gradinaru: resources, funding acquisition, and writing—review and editing. CP Venditti: conceptualization, resources, supervision, funding acquisition, and writing—review and editing. WJ Pavan: conceptualization, resources, supervision, funding acquisition, project administration, and writing—review and editing. Conflict of Interest Statement: The NIH has filed patents on behalf of RJ Chandler, CP Venditti, and WJ Pavan related to NPC1 gene therapy and biomarkers. The California Institute of Technology has filed patents related to AAV-PHP.B with BE Deverman and V Gradinaru as inventors. BE Deverman also has a patent application filed by the Broad Institute and is a consultant for Voyager Therapeutics.

Attached Files

Published - e202101040.full.pdf

Supplemental Material - LSA-2021-01040_V1.mp4

Supplemental Material - LSA-2021-01040_V2.mp4

Supplemental Material - inline-supplementary-material-1.docx

Supplemental Material - inline-supplementary-material-2.docx

Supplemental Material - inline-supplementary-material-6.docx


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August 20, 2023
December 22, 2023