A combinatorial approach for achieving CNS-selective RNAi.

Autor:	Ferguson CM; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Godinho BMDC; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Hassler M; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Vangjeli L; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Sousa J; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., McHugh N; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Alterman J; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Hariharan V; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Krishnamurthy PM; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Watts J; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Rogaev E; Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA.; Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 May 22; Vol. 52 (9), pp. 5273-5284.
DOI:	10.1093/nar/gkae100
Abstrakt:	RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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