Monitoring Treatments for ALS

via Wellcome Trust Images

Researchers have identified a protein that may act as a biomarker for amyotrophic lateral sclerosis (ALS) and could be used as a measurement for whether treatments are working. The research was published in Science Translational Medicine.

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disorder that leads to muscle atrophy, paralysis, and eventually death. The name may be familiar after a certain internet phenomenon a few years ago, The Ice Bucket Challenge, but even with an unexpected bump in funding, treatments for the disease have been slow to get off the ground. There is currently only one drug approved for use, Rillutek (riluzole), and this has only been shown to extend survival by a few months at the most.

According to the authors of this study, one of the biggest problems with trying to design new therapies for the disease is that until now there have been no known biomarkers which can be monitored to identify whether or not the treatments are working.

However, the team behind this study, led by researchers at the Mayo Clinic, have been able to show that abnormal poly(GP) proteins generated by a specific mutation in an ALS-linked gene might act as suitable markers. The proteins were identified in both cerebrospinal fluid (CSF) and peripheral blood cells of ALS patients, as well as in samples taken from carriers of the mutation who do not display symptoms of the condition. The team also found that levels of the poly(GP) proteins were decreased when drugs targeting the specific mutation were present in animal models.

“These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and pre-symptomatic individuals who are expected to benefit from early therapeutic intervention,” the authors wrote in the paper.

The type of mutation in question is a G4C2 repeat expansion; the most common genetic cause of ALS is that form of mutation occurring in the C9ORF72 gene. Other studies aimed at treating ALS have focused on trying to target the RNA molecules G4C2 mutations code for, eliminating transcripts and preventing the detrimental effects they cause. This study, however, chose instead to monitor the proteins that the same RNA molecules produce to examine whether or not the G4C2 therapies were effective.

The team were able to detect poly(GP) proteins in CSF from 134 people who have the C9ORF72 form of ALS and 27 people who are asymptomatic carriers (some of whom had other conditions including Alzheimer’s). The proteins were undetectable in 120 people who did not have the expansion mutations, 57 of whom had a different form of ALS.

Using two patient-derived cell lines, the team observed that levels of the poly(GP) proteins could be decreased significantly when the cells were treated with antisense oligonucleotides complementary to G4C2 RNA. In some cases, the protein levels were decreased by as much as 90%. Similar results were obtained when treating mouse models with C9ORF72 transcripts (c9ASOs).

The results are an indication that poly(GP) proteins may be a highly effective way of monitoring whether G4C2-targeted treatments are working in both ALS patients and asymptomatic carriers.

“Our data offer persuasive support that CSF poly(GP) represents a promising pharmacodynamic marker for c9ASOs and other therapeutic approaches, such as small molecules, that target G4C2 RNA,” the authors concluded.