Amyotrophic Lateral Sclerosis – ALS
Protein misfolding diseases
Amyotrophic Lateral Sclerosis (ALS), commonly referred to as Lou Gehrig’s disease, is an incurable, deadly neurodegenerative disease that targets the destruction of both upper and lower motor neurons. This neurological damage results in paralysis and eventually death, with an average life expectancy of three to five years after diagnosis. The short lifespan of ALS patients keeps the disease prevalence low (approximately 35,000 patients in the US), giving ALS orphaned disease status. The incidence of ALS, however, is about the same as that of multiple sclerosis, with a lifetime risk of approximately 1 in 500. As a result, any life-prolonging drug would lead to a ten-fold increase in the number of individuals needing treatment. Currently, there is only one FDA-approved treatment, which adds approximately three months to a patient’s life. New therapeutics with unique targets are therefore needed to combat the disease.
Two percent of the familial form of ALS is caused by mutations in the Cu/Zn Superoxide Dismutase (SOD), and there is growing evidence that suggests a subset (approximately 40 %) of sporadic ALS may also be caused by defects to SOD1. The prevailing theory is that modifications of SOD1 cause the protein to aggregate and gain a toxic (diseased) phenotype or function.
ExSAR is pleased to be collaborating with Brandeis University’s Dr. Jeffrey Agar, and his group’s work, in developing pharmacological chaperones based on: 1) in vivo finding in ALS patients that led to structure-based targets on the protein SOD1; and, 2) validation of these structure-based targets by demonstrating that altering their structure (by mutagenesis) resulted in greatly improved survival of primary motor neurons.