Study Points to a New Unexplored Therapeutic Target for C9ORF72-mediated ALS

A novel discovery from scientists at the ALS Therapy Development Institute (ALS TDI) is the first to indicate that asymmetric di-methylation of arginine could be a promising target for ALS therapies.

Study Points to a New Unexplored Therapeutic Target for C9ORF72-mediated ALS
Cambridge, MA, September 09, 2020 --( In a study that was recently published in Frontiers in Pharmacology, ALS TDI scientists present evidence implicating a previously unexplored therapeutic target for C9ORF72-mediated ALS. The report titled, "Type I PRMT inhibition protects against C9ORF72 arginine-rich dipeptide repeat toxicity," was authored by ALS TDI scientists, Alan Premasari, Anna Gill and Fernando Vieira, M.D.

The study demonstrated that by inhibiting Type I protein arginine methyltransferases (PRMTs), the scientists were able to protect against C9ORF72 arginine-rich dipeptide repeat toxicity. Type I PRMTs are responsible for asymmetric dimethylation of the amino acid, arginine. The results suggest that asymmetric dimethylation of C9ORF72 arginine dipeptide repeats causes them to become toxic. Inhibition of asymmetric dimethylation using small molecule Type I PRMT inhibitors was protective to cells against C9ORF72 dipeptide repeat toxicity. Thus, Type I PRMT inhibition may be protective in C9ORF72 ALS or also C9ORF72 frontotemporal dementia (FTD).

Amyotrophic lateral sclerosis, or ALS, is a progressive neurodegenerative disease. ALS attacks cells in the brain and spinal cord that are needed to keep muscles moving, leading to muscle weakness and paralysis. C9orf72 is the most common known mutation found in people with familial ALS, and has also been seen in some cases of sporadic ALS. In C9ORF72-mediated ALS, it is hypothesized that arginine rich dipeptide repeats may be toxic motor neurons. Blocking that toxicity could protect motor neurons in people with C9ORF72 ALS.

“Finding new promising treatments for ALS will require new approaches. Our discovery of the potential involvement of Type I PRMTs in C9ORF72-mediated ALS opens up entirely new and unexplored avenues for neurological drug discovery. I’m excited to advance this program and see what impact this could have on ALS,” said ALS TDI’s Chief Scientific Officer and study contributor, Fernando Vieira M.D.

The recent study builds upon findings that ALS TDI scientists published in December of 2019, demonstrating that some arginine-rich dipeptide repeat proteins resulting from C9ORF72 gene mutations are more toxic to neuronal cells than to non-neuronal cells.

Dr. Vieira noted that the discovery is most immediately relevant for patients who have the C9ORF72 mutation, however, the findings may extend to other subtypes of ALS.

The studies identified multiple small molecule drugs that were protective to cells. As next steps, ALS TDI scientists will explore asymmetric dimethylation and PRMT activity in human tissues and will work to find an optimal drug by targeting PRMTs in multiple cellular and animal models.

To learn more about ALS research at ALS TDI, visit

About the ALS Therapy Development Institute
The ALS Therapy Development Institute (ALS TDI) and its researchers discover and develop potential treatments for ALS. It is the world’s first and largest nonprofit biotech focused 100 percent on ALS research. Led by drug development experts and people with ALS, ALS TDI understands the urgent need to slow and stop this disease.

Based in Cambridge, MA, ALS TDI has more than 30 full-time, industry trained, drug development experts on staff. ALS TDI is internationally recognized as a leader in preclinical and translational ALS research, and partners with pharmaceutical companies and biotech organizations all around the world. Rated a four-star nonprofit on Charity Navigator, ALS TDI spends 87 cents of every dollar raised on finding effective treatments and cures for ALS. Visit for more information.
ALS Therapy Development Institute
Meghan Lawlor