Preferential delivery of lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide to ischemic brain in hyperacute stage.

Autor:	Li F; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Pathology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, China., Ichinose K; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan., Ishibashi S; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Internal Medicine, Fukaya Red Cross Hospital, Saitama, Japan., Yamamoto S; Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan., Iwasawa E; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan., Suzuki M; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan., Yoshida-Tanaka K; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan., Yoshioka K; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan., Nagata T; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan., Hirabayashi H; Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan., Mogushi K; Innovative Human Resource Development Division, Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan., Yokota T; Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: tak-yokota.nuro@tmd.ac.jp.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Apr 05; Vol. 31 (4), pp. 1106-1122. Date of Electronic Publication: 2023 Jan 24.
DOI:	10.1016/j.ymthe.2023.01.016
Abstrakt:	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. Competing Interests: 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. (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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