The most common genetic mutation in ALS and FTD is an abnormal repeated expansion of the coding sequence within a gene, C9ORF72, with unknown function. This mutation has been found in at least 8% of sporadic ALS and FTD cases and more than 40% of hereditary ALS and FTD cases.

"We designed experiments to find out how the repeat expansion in C9ORF72 causes cell death and disease progression," says co-senior author Dr. Rita Sattler, of Johns Hopkins University. "We used human skin cells that we obtained from patients affected with ALS and converted them into neurons via a technology called induced pluripotent stem cell production," she explains.

The researchers found that such neurons had distinct abnormalities, including dysregulated gene expression, aggregation of proteins that bind to RNA from the expansion, and susceptibility to damage from excess stimulation. These effects were reversed by blocking the RNA produced by the abnormal genetic expansion in C9ORF72. This discovery reveals how the repeated expansion in C9ORF72 may cause ALS and demonstrates the therapeutic potential of directly targeting the toxic RNA byproducts generated by the C9ORF72 expansion. "There is a great need for therapies for both ALS and FTD. We are encouraged by the new use of these stem cells to rapidly identify new treatments," says co-senior author Dr. Jeffrey Rothstein, Director of the Brain Science Institute and the Robert Packard Center for ALS research at Johns Hopkins University.

The findings indicate that RNA toxicity plays a key role in the development of ALS as well as FTD. "Future research will focus on optimizing the candidate therapies discovered by our team in this study as well as developing biomarkers that can be used to test the efficacy of other potentially promising drugs," says Dr. Rothstein