TY - JOUR
T1 - A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke
AU - Eyford, Brett A.
AU - Singh, Chaahat S.B.
AU - Abraham, Thomas
AU - Munro, Lonna
AU - Choi, Kyung Bok
AU - Hill, Tracy
AU - Hildebrandt, Rhonda
AU - Welch, Ian
AU - Vitalis, Timothy Z.
AU - Gabathuler, Reinhard
AU - Gordon, Jacob A.
AU - Adomat, Hans
AU - Guns, Emma S.T.
AU - Lu, Chieh Ju
AU - Pfeifer, Cheryl G.
AU - Tian, Mei Mei
AU - Jefferies, Wilfred A.
N1 - Funding Information:
Funding for this work was provided to WJ in the Michael Smith Laboratories, at the University of British Columbia and the Vancouver Prostate Centre, at Vancouver General Hospital, by a grant from the Canadian Institutes for Health Research (MOP-133635), a grant from the Natural Sciences and Engineering Research Council of Canada (CRDPJ 452456–13) in collaboration with Bioasis Technologies Inc. (BTI MT, [email protected]), a grant from the W. Garfield Weston Foundation (RR161038), and donations from the Sullivan Urology Foundation at Vancouver General Hospital. TA was supported by NIH grants 1S10OD010756–01A1 and
Funding Information:
We thank Terry Pearson from the University of Victoria, Department of Biochemistry for his comments on the manuscript; and Wade Edris for his technical assistance with confocal and deconvolution microscopy imaging. We also thank the National Research Council of Canada and Ava McHugh for their professional services. This manuscript was originally part of a study that has been released as a pre-print at bioRx iv (Eyford et al., 2019).
Publisher Copyright:
© Copyright © 2021 Eyford, Singh, Abraham, Munro, Choi, Hill, Hildebrandt, Welch, Vitalis, Gabathuler, Gordon, Adomat, Guns, Lu, Pfeifer, Tian and Jefferies.
PY - 2021/3/26
Y1 - 2021/3/26
N2 - 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.
AB - 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.
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U2 - 10.3389/fmolb.2021.611367
DO - 10.3389/fmolb.2021.611367
M3 - Article
C2 - 33869275
AN - SCOPUS:85104180164
SN - 2296-889X
VL - 8
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 611367
ER -