Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis

Fused in sarcoma (FUS) is an RNA-binding protein that is genetically and pathologically associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To explore the mechanisms by which mutant FUS causes neurodegeneration in ALS-FTD, we generated a series of FUS knock-in mouse lines that express the equivalent of ALS-associated mutant FUSP525L and FUSΔEX14 protein. In FUS mutant mice, we show progressive, age-dependent motor neuron loss as a consequence of a dose-dependent gain of toxic function, associated with the insolubility of FUS and related RNA-binding proteins. In this disease-relevant mouse model of ALS-FUS, we show that ION363, a…

• AA
  ALS Association
• JA
  Judith and Jean Pape Adams Charitable Foundation
• TF
  Tow Foundation
• IP
  Ionis Pharmaceuticals
• NI
  National Institute of Neurological Disorders and Stroke

  Award: 5R01NS106236