Differences in the Genetic Mutations of ALS: Anna Underhill, BS

WATCH TIME: 3 minutes

"There are very few people who have SOD1 mutation, so those treatments would only help those with SOD1. But if there’s a treatment that could target SARM1, and ifitpotentially can alleviate the effect of Wallerian degeneration, it could help in a range of cases other than just ALS caused by mutations to SARM1."

With only 2 FDA-approved therapies, there remains a significant unmet need for patients with amyotrophic lateral sclerosis (ALS). In recent years, industry leaders have begun to develop gene therapies targeted at a subset of individuals with genetically altered forms of the disease; however, the regulatory success has yet to come. One of the most prominent therapies in development, tofersen (Biogen/Ionis), an agent for the treatment of superoxide dismutase 1 (SOD1) ALS, has shown trends toward reduced disease progression and reductions in SOD1 protein in phase 3 settings; however, it did not demonstrate statistically significant functional changes on the Revised ALS Functional Rating Scale, a standard measure.

The findings beg to question whether showing a targeted reduction in these proteins truly impacts the disease course. Another genetic mutation, occurring in SARM1 and the protein it produces, has been shown to cause the death of nerve fibers and their supporting neurons. With funding help from The ALS Association, a new study will convert stem cells to neurons to create a model system that will allow further evaluation of how SARM1 variants interact with other genes and proteins in the body.

One of the trial investigators, Anna Underhill, BS, a postdoctoral researcher at King’s College London, sat down with NeurologyLive^® to discuss the complexities with seeing functional vs targeted changes. She also provided in-depth background on some of the more notable genetic mutations, how they differ from SARM1, and whether it benefits to focus drug development on one particularly dominant gene.