Preclinical evaluation of small molecules targeting C9ORF72 repeat expansion

Our therapeutic strategy aims to improve the prognosis for the largest subset of familial ALS patients – individuals carrying a mutation, or repeat expansion, in the C9ORF72 gene. By combining expertise in drug discovery, cell biology and mouse modeling, we aim to identify selective and potent compounds that can be developed into a therapy for patients suffering from C9ORF72-related diseases, which include ALS and frontotemporal dementia (c9ALS/FTD). Specifically, these compounds will target abnormal cellular processes caused by the C9ORF72 mutation and the generation of toxic ribonucleic acid (RNA) species. These RNA transcripts form clumps, termed foci, and also undergo repeat associated non-ATG (RAN) translation resulting in the production of toxic 'c9RAN proteins' unique to individuals with c9ALS/FTD. To inhibit the production of foci and c9RAN proteins, we aim to identify chemical compounds that bind to the RNA and thus prevent it from going awry. We hypothesize that therapeutically preventing c9RAN protein production and RNA foci toxicity will combat cell death and the associated disease symptoms that c9ALS/FTD patients suffer.