Study Finds New Therapeutic Target for ALS

Researchers have identified a new therapeutic approach for the most frequent cause of amyotrophic lateral sclerosis (ALS), which may also show potential for treating frontotemporal degeneration or frontotemporal dementia (FTD).

In the study, a team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer research established using segments of genetic material called antisense oligonucleotides (ASOs) to block the build-up and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.

The most common genetic cause of ALS, the authors note, is a specific gene known as C9orf72, a type of mutation that, instead of changing the protein, involves a large expansion or repeated sequence of a set of nucleotides, the basic component of RNA. Researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.

Importantly, the study also showed that toxic RNA could be removed without affecting the normal RNA that encodes the C9orf72 protein, according to investigators, adding that targeting the sense strand RNAs with a specific ASO did not impact the antisense strand foci, nor did it correct the signature of gene expression changes.

While no “major advances in the medical treatment” of ALS have been made, these findings are an example of “great strides in quality of care and supportive care,” says John Ravits, MD, clinical professor of neurosciences at UC San Diego School of Medicine and co-principal investigator.

“We hope the day will come when early diagnosis will be important for treatment and outcome.”

The study findings will appear in an upcoming issue of the journal Proceedings of the National Academy of Sciences.

—Mark McGraw