A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke.

Autor:	Eyford BA; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Singh CSB; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada., Abraham T; Department of Neural and Behavioral Sciences and Microscopy Imaging Core Lab, Pennsylvania State College of Medicine, Hershey, PA, United States., Munro L; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada., Choi KB; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada., Hill T; Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada., Hildebrandt R; Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada., Welch I; Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada., Vitalis TZ; Bioasis Technologies Inc., Guilford, CT, United States., Gabathuler R; Bioasis Technologies Inc., Guilford, CT, United States.; King's College London, London, United Kingdom., Gordon JA; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Adomat H; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Guns EST; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Lu CJ; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Pfeifer CG; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Tian MM; Bioasis Technologies Inc., Guilford, CT, United States., Jefferies WA; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.; Department of Zoology, University of British Columbia, Vancouver, BC, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2021 Mar 26; Vol. 8, pp. 611367. Date of Electronic Publication: 2021 Mar 26 (Print Publication: 2021).
DOI:	10.3389/fmolb.2021.611367
Abstrakt:	The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of neuroinflammation (NI) of the central nervous system. A twelve-amino acid peptide that transcytoses the BBB, termed MTfp, was chemically conjugated to siRNA to create a novel peptide-oligonucleotide conjugate (POC), directed to downregulate NOX4, a gene thought responsible for oxidative stress in ischemic stroke. The MTfp-NOX4 POC has the ability to cross the intact BBB and knockdown NOX4 expression in the brain. Following induction of ischemic stroke, animals pretreated with the POC exhibited significantly smaller infarcts; accompanied by increased protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp can act as a nanomule to facilitate BBB transcytosis of siRNAs; where the NOX-4 specific siRNA moiety can elicit effective therapeutic knockdown of a gene responsible for oxidative stress in the central nervous system. This study is the first to conclusively demonstrate both siRNA-carrier delivery and therapeutic efficacy in any CNS disease model where the BBB remains intact and thus offers new avenues for potential treatments of oxidative stress underlying neuroinflammation in a variety of neuropathologies that are currently refractory to existing therapies. Competing Interests: TV, RG, and MMT received funding from Bioasis Technologies Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. (Copyright © 2021 Eyford, Singh, Abraham, Munro, Choi, Hill, Hildebrandt, Welch, Vitalis, Gabathuler, Gordon, Adomat, Guns, Lu, Pfeifer, Tian and Jefferies.)
Databáze:	MEDLINE
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