Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS.

Animals Blood-Brain Barrier Central Nervous System / metabolism Cholesterol / metabolism DNA / metabolism Mice Oligonucleotides / metabolism Oligonucleotides, Antisense / therapeutic use RNA / metabolism Rats Rodentia

Journal

Nature biotechnology

ISSN: 1546-1696

Titre abrégé: Nat Biotechnol

Pays: United States

ID NLM: 9604648

Informations de publication

Date de publication:
12 2021

Historique:

received: 22 09 2020

accepted: 02 06 2021

pubmed: 14 8 2021

medline: 22 4 2022

entrez: 13 8 2021

Statut: ppublish

Résumé

Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5' end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood-brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.

Identifiants

DOI: 10.1038/s41587-021-00972-x PMID: 34385691

pubmed: 34385691

doi: 10.1038/s41587-021-00972-x

pii: 10.1038/s41587-021-00972-x

doi:

Substances chimiques

Oligonucleotides 0

Oligonucleotides, Antisense 0

RNA 63231-63-0

DNA 9007-49-2

Cholesterol 97C5T2UQ7J

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1529-1536

Informations de copyright

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