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Drug screen in iPSC-Neurons identifies nucleoside analogs as inhibitors of (G4C2)n expression in C9orf72 ALS/FTD

Cell Rep. 2022 Jun 7;39(10):110913. doi: 10.1016/j.celrep.2022.110913. PMID: 35675776.

Authors/Editors: Czuppa M, Dhingra A, Zhou Q, Schludi C, König L, Scharf E, Farny D, Dalmia A, Täger J, Castillo-Lizardo M, Katona E, Mori K, Aumer T, Schelter F, Müller M, Carell T, Kalliokoski T, Messinger J, Rizzu P, Heutink P, Edbauer D.
Publication Date: 2022


An intronic (G4C2)n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient- derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expres- sion, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with min- imal effects on global gene expression, suggesting that they specifically act on repeat transcription. Impor- tantly, decitabine treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders.



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