Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease.

Autor: Caron NS; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada., Aly AE; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada., Findlay Black H; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada., Martin DDO; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Biology, University of Waterloo, Ontario, Canada., Schmidt ME; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada., Ko S; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada., Anderson C; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada., Harvey EM; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada., Casal LL; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada., Anderson LM; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada., Rahavi SMR; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Reid GSD; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada., Oda MN; Lipotope, Inc., Fairfield, CA, USA., Stanimirovic D; Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada., Abulrob A; Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, Ontario, Canada., McBride JL; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA; Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA., Leavitt BR; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada., Hayden MR; Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: mrh@cmmt.ubc.ca.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2024 Mar; Vol. 367, pp. 27-44. Date of Electronic Publication: 2024 Jan 24.
DOI: 10.1016/j.jconrel.2024.01.011
Abstrakt: Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.
Competing Interests: Declaration of competing interest N.S.C. is a scientific consultant for GLG. D.D.O.M. is a scientific advisor for Circumvent Pharmaceuticals, Inc. M.N.O. is a scientific consultant for CymaBay Therapeutics. M.N.O. is the founder and CTO of Lipotope, Inc. B.R.L. is a scientific consultant for sRNAlytics, Teva, Roche/Genentech, Takeda, Triplet, Ionis Pharmaceuticals, Novartis, Spark Therapeutics, Sintetica, LifeEdit, Design Therapeutics, Remix Therapeutics, and PTC Therapeutics. B.R.L. is a founder and CEO of Incisive Genetics Inc. M.R.H. is the CEO of Prilenia Therapeutics, a private company, and serves on the public boards of Ionis Pharmaceuticals, Oxford Biomedica, AbCellera and 89bio. The other authors report there are no competing interests to declare.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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