ATXN2: our therapeutic target for amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis, or ALS, is a progressive and fatal neurodegenerative disease that occurs in approximately 16,000 Americans each year. Gradual onset of muscle weakness is the most common initial symptom, leading to difficulties in speaking, swallowing, and breathing. Death, typically from neuromuscular respiratory failure, generally occurs within 2 to 5 years after the appearance of initial symptoms, however, a small number of ALS patients live well beyond the three to five-year life expectancy. Current available treatments for ALS are limited and are mainly focused on providing symptomatic management and have limited impact on disease progression.
One of Maze’s founders, Aaron Gitler, identified a potent genetic modifier whose inhibition has been shown to limit the toxicity of a certain protein, TDP-43, that is involved in pathologic aggregates seen in up to 97% of all ALS cases. We are currently translating these important insights by developing a microRNA gene therapy that targets ATXN2. We have used the proprietary application of our functional genomics tools to optimize its potency and have demonstrated that knockdown of ATXN2 prolongs survival in preclinical models of ALS.