BioCentury
ARTICLE | Distillery Therapeutics

Small molecules that prevent stress granule formation in ALS

August 2, 2019 12:36 AM UTC

INDICATION: Amyotrophic lateral sclerosis (ALS)

Six compounds identified through cell-based screening could treat ALS by preventing the formation of stress granules, which have been implicated in disease pathogenesis. Small molecules from five libraries were screened for the ability to prevent stress granule formation in HEK and neural precursor cells subjected to multiple stress conditions. The screen yielded 10 compounds that inhibited stress granule formation induced by heat shock, which causes unfolded protein stress, or thapsigargin treatment, which blocks autophagic clearance of the stress granules. In human induced pluripotent stem (iPS) cell lines derived from ALS patients, six of the compounds -- including quinacrine, Novantrone mitoxantrone and pyrvinium -- reduced stress granule formation induced by sodium arsenite, thapsigargin or the antibiotic puromycin. Novantrone also reduced TDP-43 accumulation in stress granules in the ALS-patient derived cells and decreased cell death in mouse primary neurons harboring an ALS-associated mutation in TDP-43. Next steps include optimizing and testing the compounds in animal models of ALS and frontotemporal dementia, a closely related neurodegenerative disease...