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The Difference Between "A" and "U" Makes All the Difference...

Over half of ALS and FTD cases are caused by a repeat expansion in intron 1 of the C9orf72 gene.

A Completely Novel Approach: Drugging RNA with Small Molecules

Current therapeutic approaches are limited to only alleviating ALS or FTD symptoms rather than slowing or halting progression. Targeting the causative RNA expansions could be a novel way to address the root cause of the disease.

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

r(G4C2)exp C9ORF72 pre-mRNA


From Care

– to Cure


ALS & FTD are devastating and fatal neurodegenerative diseases, often caused by an expansion mutation in the C9orf72 gene

Disease Summary

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.

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.

The Expansion Therapeutics Difference

Expansion Therapeutics is taking a completely novel approach by drugging the toxic RNA with small molecules that can be orally delivered and easily cross the blood brain barrier, achieving excellent tissue distribution. We have designed small molecules that specifically target and bind to the G4C2 repeat expansion in intron 1 of C9orf72. By doing so, these drug-like molecules prevent repeat-associated non-ATG translation, and thus prevent the production of toxic poly-dipeptides. The drug-bound repeats also become more amenable to correct intronic excision, and intron 1 is thus correctly spliced out instead of being retained, subjecting the toxic RNA repeat to native decay.

Oral Delivery of Small Molecules

By orally dosing small molecules capable of crossing the blood brain barrier, patients may one day be able to simply take a pill which will address the root cause of their disease and which will slow or stop disease progression

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