New hope for ALS

Two early studies are raising hopes that some genetic forms of amyotrophic lateral sclerosis (ALS) can be treated.

Both studies investigated potential benefits of suppressing the toxic activity in cells of a mutant gene (SOD1) that encodes superoxide dismutase 1 (SOD1) in patients with ALS.

One study investigated the antisense oligonucleotide (ASO) tofersen (Biogen); the other study examined viral vector-mediated gene suppression.

The studies' promising results signal the beginning of a new precision medicine-based approach towards treating ALS

ALS is a disorder of progressive degeneration of upper and lower motor neurons. It typically leads to death from ventilatory failure within 5 years of symptom onset.

Genetic factors are responsible for about half the risk variance of ALS. In populations of European origin, variants in SOD1 account for an estimated 13% to 20% of familial ALS, although this rate varies around the world.

Although SOD1 is not the most common variant in ALS, it is the one that researchers are most familiar with and has been studied in an animal model.

An ASO is a small piece of nucleic acid that enters neurons in the spinal cord and brain.

ASO binds to the SOD1 gene and knocks down the SOD1 protein, which is the toxic engine that drives the disease, kills neurons, and causes patients to have loss of function and eventually to die.

In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.

The aim of the viral vector therapy is to continually suppress mutant gene activity.

The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis.

Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments.

In regard to ALS, by starting with subgroups that have specific genomic features, investigators are providing new hope for patients at genetic risk for this devastating fatal disease.