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

An antisense oligonucleotide targeting the RNA-binding protein FUS transcript lowers FUS levels in mice and in the central nervous system of a single patient with FUS-dependent ALS 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 FUS Delta EX14 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 non-allele-specific FUS antisense oligonucleotide, efficiently silences Fus and reduces postnatal levels of FUS protein in the brain and spinal cord, delaying motor neuron degeneration. In a patient with ALS with a FUSP525L mutation, we provide preliminary evidence that repeated intrathecal infusions of ION363 lower wild-type and mutant FUS levels in the central nervous system, resulting in a marked reduction in the burden of FUS aggregates that are a pathological hallmark of disease. In mouse genetic and human clinical studies, we provide evidence in support of FUS silencing as a therapeutic strategy in FUS-dependent ALS and FTD.

Automated summary

This study demonstrates that an antisense oligonucleotide can effectively lower the levels of FUS protein in mice and in a patient with FUS-dependent ALS. The research provides evidence that the insolubility of FUS and related RNA-binding proteins contribute to neurodegeneration in ALS-FTD. Silencing FUS using a non-allele-specific antisense oligonucleotide delays motor neuron degeneration in a disease-relevant mouse model and reduces the burden of FUS aggregates in ALS patients.