期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 617, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd5991
关键词
-
资金
- NIH [P01 NS099114, DP1 NS096898, R35 NS116846, R35 NS097273]
- Target ALS
- Nelson Family Fund
- First Family Fund
- Deutsche Forschungsgemeinschaft (DFG)
- ALS Association (ALSA)
The study developed a small molecule for targeted degradation of the G(4)C(2) RNA repeat associated with c9ALS/FTD, demonstrating selective reduction of mutant alleles and toxic proteins.
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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