NEW YORK (GenomeWeb) – Researchers have uncovered a protein that may serve as a marker for amyotrophic lateral sclerosis and could be used to ascertain whether certain treatment approaches are working.
ALS is a progressive motor neuron disease that leads to muscle atrophy, paralysis, and, often, death within a few years, but there is only one approved drug for the condition, Rillutek (riluzole), and it only lengthens survival by a few months. According to a Mayo Clinic-led team of investigators, part of the problem with developing ALS drugs is that there are no markers to indicate whether treatments are working.
In Science Translational Medicine this week, though, the Mayo team reported that abnormal poly(GP) proteins generated from a G4C2 repeat expansion in an ALS-linked gene could serve as a disease marker. Researchers led by Mayo's Leonard Petrucelli found that these proteins could be detected within cerebrospinal fluid and peripheral blood cells collected from ALS patients, as well as from asymptomatic repeat carriers. They also reported that poly(GP) protein levels changed in response to drugs targeting G4C2 RNA in both cell assays and 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," Petrucelli and his colleagues wrote in their paper.
The most common genetic cause of ALS is a G4C2 repeat expansion in the C9ORF72 gene, and researchers have been exploring the development of drugs for ALS that target G4C2 RNA. They hypothesized that eliminating these transcripts could fend off the detrimental downstream effects they have.
Petrucelli and his colleagues, meanwhile, suggested that poly(GP) proteins translated from these G4C2 RNA could act as a marker to determine whether G4C2 RNA-targeting therapeutics hit their objective.
As they reported in their paper, they were able to detect poly(GP) proteins within CSF obtained from 134 people with the C9ORF72 form of ALS, as well as within CSF from 27 asymptomatic carriers and from carriers diagnosed with other conditions, including Alzheimer's disease. Poly(GP) proteins could not be detected in CSF from 120 people without the expansion, including 57 people with a different form of ALS.
In two patient-derived cell lines, the Mayo-led researchers found that treatment with antisense oligonucleotides complementary to G4C2 RNA or C9ORF72 transcripts (c9ASOs) led to a decrease in G4C2 RNA levels and in intracellular and extracellular poly(GP) levels. Some 90 percent of poly(GP) proteins in these treated cells were lost, they noted.
Treatment with c9ASO likewise led to reduced poly(GP) level in a mouse model of C9ORF72 ALS.
This suggested to the researchers that poly(GP) levels could be monitored before and during the treatment of patients in clinical trials to gauge whether the therapy is actually hitting the G4C2 RNA target. They added that this could be particularly useful for monitoring asymptomatic mutation carriers.
"[O]ur 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," Petrucelli and his colleagues added.