Development of a molecular therapy for the SOD1 familial variant of ALS

Abstract Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an adult onset neurodegenerative disorder causing muscle atrophy and severe weakness secondary to loss of motor neurons. Patients typically die from respiratory failure after 2–5 years. There are two FDA-approved drugs to treat ALS, the benefits being modest in both instances. While the etiology for most cases of ALS is unknown, i.e., so-called "sporadic" disease, approximately 10% of cases are familial. A mutation in the superoxide dismutase 1 (SOD1) gene was the first genetic mutation to be identified as a cause of ALS. Considering the essential role of this enzyme in metabolism, it was originally thought that the degeneration of motor neurons associated with the disease was due to a loss of the enzyme's function. Ultimately, the toxicity associated with this mutation was found to be due to a “gain of function.” Subsequently, utilizing a G93A rat model of ALS, it was shown that downregulation of the SOD1 gene in a placebo-controlled trial increased the lifespan of treated animals. These results validated the potential use of antisense therapeutics as a treatment for familial ALS and similar degenerative disorders.