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

被引:47
作者
Bush, Jessica A. [1 ]
Aikawa, Haruo [1 ]
Fuerst, Rita [1 ]
Li, Yue [1 ]
Ursu, Andrei [1 ]
Meyer, Samantha M. [1 ]
Benhamou, Raphael, I [1 ]
Chen, Jonathan L. [1 ]
Khan, Tanya [1 ]
Wagner-Griffin, Sarah [1 ]
Van Meter, Montina J. [1 ]
Tong, Yuquan [1 ]
Olafson, Hailey [2 ]
McKee, Kendra K. [2 ]
Childs-Disney, Jessica L. [1 ]
Gendron, Tania F. [3 ]
Zhang, Yongjie [3 ]
Coyne, Alyssa N. [4 ]
Wang, Eric T. [2 ]
Yildirim, Ilyas [5 ]
Wang, Kye Won [5 ]
Petrucelli, Leonard [3 ]
Rothstein, Jeffrey D. [4 ]
Disney, Matthew D. [1 ]
机构
[1] Scripps Res Inst, Dept Chem, 130 Scripps Way, Jupiter, FL 33458 USA
[2] Univ Florida, Coll Med, Ctr NeuroGenet, Gainesville, FL 32610 USA
[3] Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA
[4] Johns Hopkins Univ, Robert Packard Ctr ALS Res, Sch Med, 855 North Wolfe St, Baltimore, MD 21205 USA
[5] Florida Atlantic Univ, Dept Chem & Biochem, Jupiter, FL 33458 USA
关键词
C9ORF72 HEXANUCLEOTIDE REPEAT; SEQUENCE-BASED DESIGN; RNA FOCI; ANTISENSE TRANSCRIPTS; GGGGCC REPEAT; CAG REPEATS; MOUSE MODEL; TRANSLATION; PROTEINS; GENE;
D O I
10.1126/scitranslmed.abd5991
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded G(4)C(2) RNA repeat [r(G(4)C(2))(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(G(4)C(2))(exp). The compound was able to selectively bind r(G(4)C(2))(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 reduced quantities of toxic dipeptide repeat proteins (DPRs) translated from r(G(4)C(2))(exp). In vivo work in a rodent model showed that abundance of both the mutant allele harboring the repeat expansion and DPRs were selectively reduced by this compound. These results demonstrate that targeted small-molecule degradation of r(G(4)C(2))(exp) is a strategy for mitigating c9ALS/FTD-associated pathologies and studying disease-associated pathways in preclinical models.
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页数:13
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