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 induced pluripotent stem cell (iPSC) 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).

Our strategy will help c9ALS/FTD patients by targeting 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 "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 before it goes awry. We hypothesize that therapeutically preventing c9RAN protein production and RNA foci toxicity will combat cell death and the associated disease symptoms c9ALS/FTD patients suffer.

During the grant award period, we will use a novel approach to identify and optimize highly selective small molecules that bind to the abnormal RNA. We will then subject these compounds to rigorous cell-based testing to identify those that prevent c9RAN protein production and the negative consequences of foci formation. Of importance, to provide assurance that our therapeutic strategy will be effective in humans, lead compounds will be tested in human neuronal cultures derived from c9ALS/FTD patient iPSCs. In addition, a mouse model of c9ALS/FTD will be generated in order to better understand the role of foci and c9RAN proteins in disease and to provide a preclinical model for testing lead compounds. Following successful completion of the proposed studies, we aim to begin the necessary steps for bringing our treatment strategy to clinical trial.

In conducting this multi-screen approach, our goal is to advance the development of therapeutics for ALS patients having the C9ORF72 mutation, the most common genetic cause of ALS.