Publications

Dernière publication 24/01/2022

Antisense oligonucleotide silencing of FUS expression as a therapeutic approach

Fused in sarcoma (FUS) is an RNA-binding protein that is genetically and pathologically associated with rare and aggressive forms of amyotrophic...

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    [title] => Antisense oligonucleotide silencing of FUS expression as a therapeutic approach 
    [paragraph] => Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis
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Authors
VA Korobeynikov, AK Lyashchenko

 Lab
Columbia University, New York, NY, USA
Journal
Nature Medicine
Abstract
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_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.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)
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Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
Nouveautés GS4 - 2023: Écran couleur rétroéclairé (meilleure lisibilité), pédale de remise à zéro, durée de batterie optimisée, taille de mémoire augmentée à 500 valeurs, compteur d'animaux, port USB (transfert de données/charge)

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