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

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.

Unlocking the Complexity of Neuromuscular Diseases: Insights from Human Pluripotent Stem Cell-Derived Neuromuscular Junctions

“…Surprisingly, these observations are different from studies generated with hiPS-derived MNs from SMA patients [79][80][81]. In their study, the authors observed a 50% loss of survival of MNs after 8 weeks in culture.…”

A novel microbe-drug association prediction model based on graph attention networks and bilayer random forest

“…The second drug we have selected is moxifloxacin, a quinolone broad-spectrum antimicrobial that treats adults (≥ 18 years of age) suffering from respiratory tract infections, both upper and lower [ 29 ], as well as acute sinusitis [ 30 ], acute exacerbations of chronic bronchitis [ 31 ], community-acquired pneumonia [ 32 ], and skin and soft tissue infections [ 33 ]. Januel et al [ 34 ] studied the use of moxifloxacin to treat the genetic disorder spinal muscular atrophy (SMA). However, Inada et al [ 35 ] found that moxifloxacin can induce aortic aneurysms and clips by increasing bone bridging proteins in mice.…”

Avances terapeúticos en atrofia muscular espinal

“…Se encuentra en actual estudio con ratones, dentro de los cuales se han obtenido resultados alentadores frente a la inducción en células madre pluripotentes, sobre todo en los tipos de AME 1 y 2. Al posicionarse como posible tratamiento demuestra que se pueden descubrir nuevas terapias para enfermedades raras, enriqueciendo las opciones médicas, tanto como terapias independientes o para completar terapias que ya han sido usadas (22). Cas9.…”