Preferential delivery of lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide to ischemic brain in hyperacute stage.
drug delivery
gene-silencing efficacy
heteroduplex oligonucleotide
hyperacute ischemic stroke
lipoprotein receptor
receptor-mediated transcytosis
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 04 2023
05 04 2023
Historique:
received:
15
03
2021
revised:
21
11
2022
accepted:
19
01
2023
pmc-release:
05
04
2024
medline:
10
4
2023
pubmed:
26
1
2023
entrez:
25
1
2023
Statut:
ppublish
Résumé
Antisense oligonucleotide (ASO) is a major tool used for silencing pathogenic genes. For stroke in the hyperacute stage, however, the ability of ASO to regulate genes is limited by its poor delivery to the ischemic brain owing to sudden occlusion of the supplying artery. Here we show that, in a mouse model of permanent ischemic stroke, lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide (lipid-HDO) was unexpectedly delivered 9.6 times more efficiently to the ischemic area of the brain than to the contralateral non-ischemic brain and achieved robust gene knockdown and change of stroke phenotype, despite a 90% decrease in cerebral blood flow in the 3 h after occlusion. This delivery to neurons was mediated via receptor-mediated transcytosis by lipoprotein receptors in brain endothelial cells, the expression of which was significantly upregulated after ischemia. This study provides proof-of-concept that lipid-HDO is a promising gene-silencing technology for stroke treatment in the hyperacute stage.
Identifiants
pubmed: 36694463
pii: S1525-0016(23)00016-3
doi: 10.1016/j.ymthe.2023.01.016
pmc: PMC10124084
pii:
doi:
Substances chimiques
Oligonucleotides
0
RNA
63231-63-0
Ligands
0
Oligonucleotides, Antisense
0
DNA
9007-49-2
Lipids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1106-1122Informations de copyright
Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests T.Y. collaborates with Daiichi Sankyo Company, Ltd.; Rena Therapeutics Inc.; Takeda Pharmaceutical Company, Ltd.; and Toray Industries, Inc., in addition to serving as an academic adviser for Rena Therapeutics Inc. and Braizon Therapeutics Inc. All other authors declare no competing interests.
Références
Pharm Res. 2006 Jun;23(6):1251-64
pubmed: 16718617
RNA Biol. 2017 Dec 2;14(12):1705-1714
pubmed: 28837398
Stroke. 2003 Nov;34(11):2750-62
pubmed: 14576375
Circ Res. 2014 Apr 25;114(9):1389-97
pubmed: 24602777
J Mol Neurosci. 2011 Jun;44(2):130-9
pubmed: 21318404
Lancet Neurol. 2011 Oct;10(10):909-21
pubmed: 21939900
Neuroscience. 2016 Nov 19;337:191-199
pubmed: 27651151
J Neurosci. 2015 Dec 16;35(50):16443-9
pubmed: 26674869
J Vasc Interv Neurol. 2008 Oct;1(4):91-5
pubmed: 22518231
Sci Rep. 2018 Mar 12;8(1):4377
pubmed: 29531265
J Clin Invest. 2020 Jun 1;130(6):2777-2788
pubmed: 32391806
J Cell Mol Med. 2019 Apr;23(4):2970-2983
pubmed: 30784209
Nat Commun. 2015 Aug 10;6:7969
pubmed: 26258894
J Mol Neurosci. 2012 Nov;48(3):550-7
pubmed: 22460784
Free Radic Biol Med. 1992;13(1):55-74
pubmed: 1628854
FEBS Lett. 2020 May;594(9):1413-1423
pubmed: 31990989
J Neurochem. 2000 Nov;75(5):1970-6
pubmed: 11032886
Eur Heart J. 2015 Sep 14;36(35):2373-80
pubmed: 26071599
J Cereb Blood Flow Metab. 2009 Mar;29(3):606-20
pubmed: 19107136
Exp Neurol. 2016 Mar;277:162-170
pubmed: 26746985
Neuron. 2010 Jul 29;67(2):181-98
pubmed: 20670828
Mol Aspects Med. 2007 Oct-Dec;28(5-6):423-36
pubmed: 17320165
Nat Biotechnol. 2021 Dec;39(12):1529-1536
pubmed: 34385691
Front Neurol. 2015 Mar 13;6:50
pubmed: 25821444
Neuron. 2012 Jun 21;74(6):1031-44
pubmed: 22726834
Nucleic Acids Res. 2019 Aug 22;47(14):7321-7332
pubmed: 31214713
Biochem Biophys Res Commun. 2013 Jan 25;430(4):1201-5
pubmed: 23268342
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5633-8
pubmed: 10805816
Neuropharmacology. 2020 Oct 1;176:108202
pubmed: 32615189
J Neurosci. 2017 Feb 15;37(7):1797-1806
pubmed: 28093478
Brain Res Brain Res Rev. 2001 Dec;38(1-2):140-8
pubmed: 11750930
Front Cell Neurosci. 2014 Aug 14;8:231
pubmed: 25177270
Anesthesiology. 2000 Oct;93(4):1085-94
pubmed: 11020765
N Engl J Med. 1995 Dec 14;333(24):1581-7
pubmed: 7477192
Stroke. 2012 Oct;43(10):2800-2
pubmed: 22949471
Artif Organs. 2014 Aug;38(8):662-6
pubmed: 25295359
Cell Physiol Biochem. 2017;43(1):182-194
pubmed: 28854438
Int J Mol Sci. 2018 Jun 11;19(6):
pubmed: 29891768
Cell Death Dis. 2018 Feb 15;9(3):281
pubmed: 29449542
Nat Med. 2013 Dec;19(12):1584-96
pubmed: 24309662
Neurophotonics. 2019 Oct;6(4):045012
pubmed: 31824979
Radiol Oncol. 2018 Dec 20;53(1):25-30
pubmed: 30864425
PLoS One. 2015 Sep 14;10(9):e0138029
pubmed: 26367258
Adv Pharmacol. 2014;71:165-202
pubmed: 25307217
Hum Gene Ther. 2013 May;24(5):489-98
pubmed: 23544870
Mol Neurobiol. 2017 Dec;54(10):7670-7685
pubmed: 27844279
Chem Rev. 2007 Nov;107(11):4672-97
pubmed: 17944519
Neuron. 2014 May 7;82(3):603-17
pubmed: 24746419