Genetic mutations involving repeat expansions in the C9ORF72 gene are the most common genetic causes of ALS and FTD. The faulty gene creates repeating RNAs that are transported from the cell’s nucleus into the cytoplasm where they generate toxic proteins known as dipeptide repeat proteins (DPRs). In addition, in several neurodegenerative diseases including ALS and Alzheimer’s disease, toxic TDP-43 aggregates are a frequent hallmark of disease. TDP-43 mislocalization the cytosol of neurons leads to RNA dysfunction and cytotoxicity. Pathology involving TDP-43 is present in 97% of patients with ALS, 50% of patients with FTD, up to 57% of Alzheimer’s patients and up to 7% of patients with Parkinson’s disease.

Crucible is developing novel therapies that prevent rogue RNAs from escaping into the cytoplasm where they become toxic and damage cells.  Our approach disrupts the production of both toxic dipeptide repeats (DPRs) and TDP-43 aggregates meaning that is relevant for both C9ORF72- and Sporadic-ALS populations and other neurodegenerative diseases. Production of toxic DPRs is predicted to be the major cause of disease progression in patients who possess the C9ORF72 mutation, whilst TDP-43 mislocalisation and aggregation occurs in 97% of ALS patients.

In recent years, RNA interference (RNAi) has become an established technology that can reliably rid patients of disease-causing or disease-enabling genes or proteins. RNAi therapies can be delivered to patients as short-interfering RNAs (siRNA) or as short-hairpin RNAs with the latter typically being delivered as part of a viral vector (e.g. AAV). Crucible is pursuing both approaches for the treatment of ALS, FTD and other neurodegenerative diseases.