Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(G₄C₂) repeat expansion in vitro and in vivo ALS models.

ABSTRACT: The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded G₄C₂ RNA repeat [r(G₄C₂)^exp] in chromosome 9 open reading frame 72 (C9orf72), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(G₄C₂)^exp. The compound was able to selectively bind r(G₄C₂)^exp’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms. In c9ALS patient–derived spinal neurons, the compound selectively degraded the mutant C9orf72 allele with limited off-targets and re

SUBMITTER: Bush JA 

PROVIDER: S-EPMC9533739 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature