Emerging drug targets in amyotrophic lateral sclerosis

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease resulting from injury and death of upper and lower motor neurons. Symptoms initially include muscle weakness and twitching and subsequently progress to muscle atrophy, complete loss of limb use, respiratory difficulties and ultimately death. Multiple biological mechanisms have been implicated in ALS and a complex etiology has been described. As a result, drug discovery researchers have few validated targets to pursue and patients have few therapeutic options. Areas covered: Identification of new drug targets in ALS can be facilitated by a detailed understanding of the processes and genes that contribute to pathogenesis. Accordingly, this review summarizes current hypotheses regarding underlying mechanisms for motor neuron susceptibility in ALS. An overview of emerging and tractable drug targets that could result in therapeutic breakthroughs is provided. Expert opinion: Despite the immense progress that has been made in understanding ALS over the last decade, riluzole remains the only approved drug to treat ALS. Combining structure-guided drug design applied to validated and pharmaceutically tractable targets with disease-relevant phenotypic screens will allow for the identification of novel drug targets and potentially breakthrough therapeutics for ALS.