Moxifloxacin Boosts SMN Levels, Lifespan in SMA Cell, Mouse Models

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by Marisa Wexler MS |

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Moxifloxacin, an antibiotic with a well-established safety profile, boosted production of the SMN protein in cellular models of spinal muscular atrophy (SMA) and it extended the lifespan and improved motor function in mice with the disease, a new study reports.

“Preclinical data from patient-derived MNs [motor neurons] and a severe SMA mouse model encourage the clinical repurposing of” moxifloxacin for SMA, its researchers wrote.

The study, “Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model,” was published in Cellular and Molecular Life Sciences.

SMA is caused by mutations in the SMN1 gene, which provides instructions for making a protein called SMN that’s critical for the function and survival of motor neurons, the nerve cells that control movement. Another gene, called SMN2, also encodes the SMN protein, but due to differences in how the two genes are “read,” the SMN2 gene normally doesn’t produce substantial amounts of protein.

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Modulating the activity of the SMN2 gene to boost SMN protein production is an established SMA therapeutic strategy — two currently approved therapies, Spinraza (nusinersen) and Evrysdi (risdiplam), both work via this mechanism of action.

“Despite the remarkable efficiency of these treatments, they also present disadvantages in administration method, patient exclusion criteria, or access due to the therapy’s high cost,” the researchers wrote. “Moreover, the limited data on the long-term efficacy and safety of these innovative therapies makes it crucial to continue to search for alternative, backup treatments for SMA.”

In a previous study, the international team of scientists conducted a screen in a fruit fly model and identified moxifloxacin as a potential modulator of SMN2. Moxifloxacin is an antibiotic sold under the brand name Avelox and in generic formulations. It’s been approved in the U.S. to treat bacterial infections since the 1990s. Since it’s an older medication that’s been in use for decades, the safety and pharmacological profile of moxifloxacin is well established.

“The well-known profile of this drug makes it an exciting candidate for a clinical trial,” the researchers wrote.

The scientists tested cell and animal models to further explore moxifloxacin as a potential SMA treatment.

The team first conducted experiments in iPSC-derived motor neurons from people with or without SMA. This involved collecting skin cells from patients then using established biochemical manipulations to grow them into stem cells called iPSCs, which can then be prompted to grow into motor neurons.

Results showed that treating SMA motor neurons with moxifloxacin boosted the production of SMN protein and increased the cells’ survival. Experiments of iPSC-derived motor neurons grown in culture with muscle cells showed moxifloxacin treatment also increased neurons’ ability to form signaling connections with the muscle (neuromuscular junctions, or NMJs)

“The SMN levels after moxifloxacin treatment are lower than the SMN wild-type levels; nevertheless, the survival rates of wild-type and treated cells are very similar,” the researchers wrote. “Notably, the survival rate and the SMN protein levels after moxifloxacin treatment are above the results obtained with the current first-line drug risdiplam [Evrysdi].”

The scientists next tested moxifloxacin in a mouse model of severe SMA called the delta 7 model. Mice were treated with either moxifloxacin or an inactive vehicle solution, given via daily injections under the skin.

Results showed mice treated with moxifloxacin had significantly higher body weights and performed significantly better on standardized measures of muscle strength, reflexes, and coordination.

“Overall, these results suggest a general improvement in the health (weight gain), and strength and motor coordination (behavioural tests) of the skeletal muscles of SMA mice upon moxifloxacin administration compared to control animals,” the researchers wrote.

Treatment with moxifloxacin extended median survival time significantly. Treated mice lived 15 days, compared to 13 days in their untreated counterparts.

Moxifloxacin treatment boosted SMN protein production in the spinal cord and in muscles, analyses of the mice’s tissue indicated. Treated mice also showed fewer signs of motor neuron death and dysfunction, less neuroinflammation, and reduced muscle atrophy, as well as signs of healthier NMJs.

“Overall, such muscle and NMJ phenotype ameliorations justify the positive results obtained in the body weight assessment and the behavioural tests, highlighting the reduced muscle atrophy and the improved motor performances (in terms of posture, strength, and coordination), compared to the control group,” the scientists concluded.

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