Gene Therapy Holds Promise to Treat ALS Caused by SOD1 Mutations, Preclinical Study Shows

An experimental gene therapy based on RNA interference (RNAi) shows potential to treat patients with familial amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene, according to results of a preclinical study in nonhuman primates.

The study, “Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques,” was published in the journal Science Translational Medicine.

About 20 percent of familial, or inherited, ALS cases worldwide are caused by mutations in the SOD1 gene. These mutations result in the production and accumulation of toxic SOD1 protein, leading to the progressive loss of motor nerve cells in the brain and the spinal cord.

Several studies have shown that reducing the levels of SOD1 in mice with SOD1 mutations — used as a model of SOD1-associated ALS — reduces nerve cell damage, improves their motor and respiratory function, and prolongs their survival.

So researchers have been working on the development of therapeutic approaches to reduce the levels of SOD1 in ALS patients with mutations in this gene.

RNAi is a natural process of gene silencing that regulates gene expression, in which microRNA (miRNA) molecules bind to a specific messenger RNA (mRNA) — the molecule generated from DNA that is the template for the production of a specific protein — targeting it for destruction, ultimately preventing the production of that protein.

Since specific miRNA molecules can be designed for any given gene and a single molecule is able to silence many target mRNAs, RNAi therapy has the potential to prevent or reverse neurodegeneration in SOD1-associated ALS.

Researchers have now evaluated the safety and effectiveness of an RNAi-based gene therapy targeting SOD1 mRNA levels in cynomolgus macaques, a type of primate. This therapy has the advantage of requiring only a one-time administration.

The therapy consisted of miRNA molecules designed to target the mRNA of the SOD1 gene (SOD1-miRNA) and delivered through a modified and harmless adeno-associated virus (AAV). The chosen AAV — rAAVrh.10 — was previously shown to work well in the central nervous system (brain and spinal cord) and to be safe in clinical trials.

Different versions of components inserted in the AAV and involved in the production of miRNAs were tested to identify the one inducing the higher levels of SOD1-miRNA molecules.

Researchers administered the therapy directly into the spinal cord (intrathecal administration) of the animals, and analyzed the mRNA levels, or the expression, of SOD1, in three distinct areas of the spinal cord.

The data showed that SOD1-miRNA molecules were successfully delivered not only to the spinal cord and brain, but also to peripheral organs, highlighting the therapy’s potential to induce widespread therapeutic effects throughout the body and achieve better overall results.

The high levels of SOD1-miRNA detected in the spinal cord led to a significant reduction of SOD1 expression throughout its length, and in motor nerve cells.

There was also a strong association between the levels of SOD1-miRNA molecules and the subsequent reduction of SOD1 expression (protein production), with the best AAV version achieving up to a 93% reduction of SOD1 mRNA levels in the spinal cord.

The intrathecal administration of this RNAi-based gene therapy was safe and well-tolerated by the primates during follow-up (up to 92 days) and was not associated with any safety concerns.

“These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1-linked ALS,” the researchers wrote.

They also noted that the U.S. Food and Drug Administration recently approved an investigational drug application of this therapy to begin a pilot Phase 1 clinical trial in humans. The trial will evaluate whether the therapy’s safety profile in humans is similar to that found in nonhuman primates.