2. Academic Validation
  3. Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

  • Cell Mol Life Sci. 2022 Jul 22;79(8):441. doi: 10.1007/s00018-022-04450-8.
Camille Januel  # 1,  Giovanna Menduti  # 2,  Kamel Mamchaoui 3,  Cecile Martinat 4,  Ruben Artero 5 6,  Piotr Konieczny  # 7 8,  Marina Boido  # 2
Affiliations

Affiliations

  • 1 INSERM/UEVE, UMR 861, Université Paris Saclay, I-STEM, AFM-Telethon, Rue Henri Desbruères, 91100, Corbeil-Essonnes, France.
  • 2 Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Regione Gonzole 10, Orbassano, 10043, Turin, TO, Italy.
  • 3 Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, 75013, Paris, France.
  • 4 INSERM/UEVE, UMR 861, Université Paris Saclay, I-STEM, AFM-Telethon, Rue Henri Desbruères, 91100, Corbeil-Essonnes, France. cmartinat@istem.fr.
  • 5 University Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Street Dr. Moliner, 50, 46100, Burjasot, Valencia, Spain. ruben.artero@uv.es.
  • 6 Translational Genomics Group, Incliva Biomedical Research Institute, Avenue Menéndez Pelayo 4 acc, 46010, Valencia, Spain. ruben.artero@uv.es.
  • 7 University Institute of Biotechnology and Biomedicine (BIOTECMED), Universitat de València, Street Dr. Moliner, 50, 46100, Burjasot, Valencia, Spain.
  • 8 Translational Genomics Group, Incliva Biomedical Research Institute, Avenue Menéndez Pelayo 4 acc, 46010, Valencia, Spain.
  • # Contributed equally.
PMID: 35864358 DOI: 10.1007/s00018-022-04450-8
Abstract

Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an Antibiotic, can be potentially repositioned for the SMA treatment.

Keywords

Drug repurposing; Motoneurons; SMA delta7 mice; SMN2 splicing; Spinal muscular atrophy.

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