ALS (amyotrophic lateral sclerosis) and FTD (fronto-temporal dementia) are neurodegenerative diseases that dramatically impact quality of life and lifespan. ALS is a motor disease, featuring muscle weakness and paralysis, loss of speech, and respiratory insufficiency. FTD is a severe form of dementia, often presenting initially as changes in personality and rapidly progressing to memory loss, cognitive dysfunction, and psychiatric disturbances.  Occasionally, a mixed presentation of both motor and cognitive symptoms is observed (ALS/FTD). There are approximately 12,000-15,000 ALS patients in the US, and an additional 50,000-60,000 who have FTD. 

In approximately half of all cases of either ALS or FTD, the genetic cause has been identified to be a mutation in the C9orf72 gene. In the first intron of this gene, a hexo-nucleotide expansion (G4C2) occurs, such that hundreds of these repeats are present. These repeating sequences are transcribed into RNA and form abnormal structures.  Because of these structures, this intron containing the expansion repeats is aberrantly retained within the mRNA, rather than being spliced out (which is what normally occurs). The resulting mRNA is then subject to an abnormal form of translation, repeat-associated non-ATG translation (RANT). This RAN translation results in the production of multiple types of poly-dipeptides that have been shown to exert neuronal toxicity and cause disease. Thus, both ALS and FTD related to C9orf72 are RNA-mediated diseases.

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Current therapeutic approaches are very limited. The advent of antisense oligonucleotides (ASOs) has demonstrated that targeting the RNA expansions is a viable approach, preclinically. However, ASOs are difficult to deliver to the central nervous system and have limited distribution within the brain; separate administrations would be needed to target other relevant organs e.g. muscle.