uc-sanUniversity of California, San Diego School of Medicine and Ludwig Institute for Cancer Research scientists and researchers have reportedly spotlighted a novel therapeutic approach to address the most frequent genetic cause of amyotrophic lateral sclerosis (ALS).

The study, appearing in the online edition of PNAS, indicates the use of antisense oligonucleotides (ASOs) to block the buildup and selectively degrade toxic RNA reported to contribute to the most common form of ALS, without impacting the normal RNA produced from the same gene.

A news release from the University of California, San Diego Health Sciences notes that in 2011, a specific gene known as C9orf72 was found to be the most common genetic cause of ALS. Normal C9orf72 genes contain fewer than 30 of the nucleotide repeat unit, GGGGCC. Researchers explain that the mutant gene may contain hundred of repeats of this unit, generating a repeat containing RNA that aggregate into foci.

In the release, the researchers also report that they discovered changes in expression of other genes that accompanies expression of repeat-containing RNAs. Since reducing the level of expression of C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the release states, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.

First author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego department of Neurosciences and Ludwig Institute for Cancer Research, notes that this finding, “led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein…”

Despite the promising results, Lagier-Tourenne notes that targeting the sense strand RNAs with a specific ASO did not impact the antisense stand foci or correct the signature gene expression changes.

However, John Ravits, MD, UC San Diego department of Neuorsciences states that, “our study also demonstrates the—to now—unrecognized role of antisense RNA and its potential as a therapeutic target.”

Source: University of California, San Diego School of Medicine