Press Release

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

March 6, 2023

Abstract

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.

Journal Article

JOURNAL: Molecular Therapy

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

DOIhttps://doi.org/10.1016/j.ymthe.2023.01.016

Correspondence to

  1. Takanori Yokota, MD, PhD, Professor

    Department of Neurology and Neurological Science,
    Graduate School of Medical and Dental Sciences,
    Tokyo Medical and Dental University (TMDU)
    E-mail: tak-yokota.nuro(at) tmd.ac.jp

    *Please change (at) in the e-mail addresses to @ when sending correspondence.