RARE Daily

Targeting Genetic Mutations to Treat ALS

July 9, 2020

A growing body of evidence points to mutations within multiple genes that are believed to underlie amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, a progressive disorder that impacts nerve cells in the brain and spinal cord leading to reduced muscle function, loss of muscle control, and eventually death. Average life expectancy is three years, and there is currently no cure for the disease.

Many companies are working on finding a cure and among a growing list of potential ways to target the debilitating condition, two studies recently published in the New England Journal of Medicine, along with an accompanying editorial, describe genetic approaches to potential therapies that may hold promise.

ALS can be traced to mutations in more than 25 different genes and is often caused by a combination of multiple sub-forms of the condition. Mutations in the gene SOD1, the second most common genetic form of ALS, were discovered more than 20 years ago and are the focus of the recently published studies, both of which took different gene silencing approaches to address the effects of down-regulating the expression of the mutated SOD1 gene in ALS patients with that mutation. Although neither study was powered to demonstrate efficacy, both showed that gene silencing has potential as a treatment for ALS patients with SOD1 mutations.

“These advances signal a new beginning for ALS therapeutics in which some forms of the disease may become treatable,” write the authors of the editorial, Orla Hardiman, clinical professor of neurology at Trinity College in Dublin and Leonard van den Berg, of the University Medical Center at Utrecht in the Netherlands. “By starting with subgroups with specific genomic features, investigators are providing new hope for patients at genetic risk for this devastating fatal disease.”

In one study, researchers used an AAV to insert a microRNA targeting SOD1 via intrathecal infusion into two patients with familial ALS and mutations in the SOD1 gene. The first patient died from an adverse reaction to the AAV but at postmortem autopsy, SOD1 levels in spinal cord tissue were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. The second patient was pretreated with immunosuppressive drugs and didn’t have a similar adverse reaction to the AAV. That patient had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. Although much additional work needs to be done on whether biologic and clinical efficacy can be achieved, the study did demonstrate that intrathecal microRNA could be a potential treatment for SOD1-mediated ALS.

The other published study, an early-phase trial of Biogen’s tofersen, an antisense oligonucleotide licensed from Ionis Pharmaceuticals, was a dose ranging placebo controlled trial in 48 patients designed to evaluate the safety, tolerability, and pharmacokinetics of four different doses of the drug. While efficacy was not measured directly, the secondary outcome of reductions in SOD1 levels in cerebrospinal fluid is promising. Treatment with the highest dose of tofersen in ten patients over a three-month period resulted in a 36 percent reduction of SOD1 concentration compared to 3 percent in the placebo group of 12 patients.

There was also a trend towards slowing of clinical decline as measured by the ALS Functional Rating Scale Revised (ALSFRS-R) as well as slow vital capacity and muscle strength measured by handheld dynamometer (HHD) compared to placebo. The mean change in ALSFRS-R score from baseline to day 85 was -1.19 in the tofersen 100 mg group compared to -5.63 in the placebo group on a 48-point scale. Across exploratory clinical measures, separation from the placebo group was primarily driven by the fast-progressing subgroup.

The most commonly reported adverse events in the 38 patients who received one or more doses of tofersen were headache, procedural pain, post-lumbar puncture syndrome, and falls. Five tofersen- and two placebo-treated people experienced serious adverse events. One death occurred in the placebo group during the trial due to respiratory failure secondary to ALS and two deaths occurred in the tofersen group during a follow up period due to pulmonary embolism and respiratory failure.

Biogen is currently testing tofersen in an ongoing phase 3 study to assess its efficacy and safety versus placebo in adults with SOD1-ALS.

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