One Study Explores Genetic Editing for C9orf72-Related ALS and Frontotemporal Dementia

A study by Aradhana Sachdev and colleagues, published on April 23, 2024, in the Proceedings of the National Academy of Sciences of the United States of America, sheds light on potential genetic interventions for conditions linked to the C9orf72 gene, a major contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The research, conducted at the Gladstone Institutes in San Francisco, CA, investigates how specific genetic modifications can reverse harmful effects associated with the C9orf72 mutation in human neurons.

The C9orf72 gene is known for its complex structure and the presence of a repeat expansion that can lead to toxic protein production, contributing to neurodegenerative diseases. In this study, the researchers created five different genetic edits in both patient-derived stem cells with the C9orf72 mutation and healthy control cells. This allowed them to compare the effects of these edits on gene expression and the pathological features of ALS and FTD.

One of the key findings was that the mutant allele of the C9orf72 gene was producing significantly more harmful RNA than the normal allele—at least ten times more. The researchers discovered that removing the mutant repeat expansion not only corrected RNA abnormalities but also eliminated the production of toxic dipeptide repeat proteins, which are believed to contribute to neuronal damage. Additionally, the edited neurons showed improved electrical activity, indicating better functional performance.

However, the study also revealed some unexpected results. For instance, when the normal allele was excised, the expression of certain toxic proteins from the mutant allele actually increased. This suggests that the relationship between the two alleles is more complex than previously understood, highlighting the need for careful consideration in developing gene therapies.

While the results are promising, the study does have limitations. The findings are based on a single patient-derived cell line, and further research is needed to confirm these results across different genetic backgrounds and in more diverse patient populations.

Overall, this study enhances our understanding of the C9orf72 gene's role in ALS and FTD and opens the door for future research into targeted gene therapies. The insights gained could inform the development of new treatments aimed at mitigating the effects of this mutation, potentially leading to more effective interventions for those affected by these challenging conditions.