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

Topic: Brain proteins, microglia and lab models

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 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.

@article{korben2022-35075293,
  author  = {Korben, V. A. and Lyashchenko, A. K. and Blanco-Redondo, B. and Jafar-Nejad, P. and Shneider, N. A.},
  title   = {{Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis}},
  journal = {Nature medicine},
  year    = {2022},
  doi     = {10.1038/s41591-021-01615-z},
  pmid    = {35075293},
  url     = {https://doi.org/10.1038/s41591-021-01615-z}
}

Key findings

• 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).
• 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.

Why it matters

In FUS mutant mice, the antisense oligonucleotide ION363 silenced Fus and delayed motor neuron degeneration, and one patient with ALS with a FUSP525L mutation received preliminary evidence of reduced FUS levels after repeated intrathecal infusions. This is an animal and single-patient preliminary study relevant to FUS-dependent ALS and frontotemporal dementia, not a demonstrated treatment, cure, or prevention for Alzheimer's disease.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41591-021-01615-z
• PubMed: 35075293
• Original source →
• Free full text: Nature Medicine →

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• The role of FUS gene variants in neurodegenerative diseases Nature reviews. Neurology · 2014-05-20 · usefulness score 49/100 · Lewy body dementia

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