Frontiers in Molecular Biosciences (Mar 2021)
A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke
- Brett A. Eyford,
- Brett A. Eyford,
- Brett A. Eyford,
- Brett A. Eyford,
- Chaahat S. B. Singh,
- Chaahat S. B. Singh,
- Chaahat S. B. Singh,
- Chaahat S. B. Singh,
- Chaahat S. B. Singh,
- Thomas Abraham,
- Lonna Munro,
- Lonna Munro,
- Kyung Bok Choi,
- Kyung Bok Choi,
- Tracy Hill,
- Rhonda Hildebrandt,
- Ian Welch,
- Timothy Z. Vitalis,
- Reinhard Gabathuler,
- Reinhard Gabathuler,
- Jacob A. Gordon,
- Jacob A. Gordon,
- Hans Adomat,
- Hans Adomat,
- Emma S.T. Guns,
- Emma S.T. Guns,
- Chieh-Ju Lu,
- Chieh-Ju Lu,
- Chieh-Ju Lu,
- Chieh-Ju Lu,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Mei Mei Tian,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies
Affiliations
- Brett A. Eyford
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Brett A. Eyford
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Brett A. Eyford
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Brett A. Eyford
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Chaahat S. B. Singh
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Chaahat S. B. Singh
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Chaahat S. B. Singh
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Chaahat S. B. Singh
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Chaahat S. B. Singh
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Thomas Abraham
- Department of Neural and Behavioral Sciences and Microscopy Imaging Core Lab, Pennsylvania State College of Medicine, Hershey, PA, United States
- Lonna Munro
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Tracy Hill
- Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada
- Rhonda Hildebrandt
- Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada
- Ian Welch
- Centre for Comparative Medicine, University of British Columbia, Vancouver, BC, Canada
- Timothy Z. Vitalis
- Bioasis Technologies Inc., Guilford, CT, United States
- Reinhard Gabathuler
- Bioasis Technologies Inc., Guilford, CT, United States
- Reinhard Gabathuler
- 0King’s College London, London, United Kingdom
- Jacob A. Gordon
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Jacob A. Gordon
- 1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Hans Adomat
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Hans Adomat
- 1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Emma S.T. Guns
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Emma S.T. Guns
- 1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Chieh-Ju Lu
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Chieh-Ju Lu
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Chieh-Ju Lu
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Chieh-Ju Lu
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Mei Mei Tian
- Bioasis Technologies Inc., Guilford, CT, United States
- Wilfred A. Jefferies
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- 1Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- 2Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- 3Department of Zoology, University of British Columbia, Vancouver, BC, Canada
- DOI
- https://doi.org/10.3389/fmolb.2021.611367
- Journal volume & issue
-
Vol. 8
Abstract
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.
Keywords
