Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene, which provides instructions for making the survival motor neuron (SMN) protein. These mutations lead to not enough SMN protein being produced causing impaired neuronal function and subsequently impaired muscle function.

In addition to therapies aimed at addressing the underlying genetic cause of the disease, directly targeting muscles to improve their function could also be beneficial for patients. The most promising approaches include exercise and physiotherapy, myostatin inhibition, fast muscle troponin complex activation, and cholinesterase inhibition.

Exercise and physiotherapy

In a mouse model of mild SMA, long-term exercise such as running and swimming was shown to significantly improve grip strength, motor neuron survival, muscle resistance to damage, and the structure of neuromuscular junctions, the point where nerve and muscle cells meet. 

An innovative physiotherapeutic approach, based on physical training in a swimming pool, is currently being investigated in a pilot study (NCT02061189) to assess its potential effect in improving motor function in people with SMA.

Another potential treatment is so-called whole body vibration therapy (WBVT), which has been suggested to have beneficial effects on muscle function in healthy adults and post-menopausal women. There have also been studies on the effects of WBVT in children with muscular dystrophies. These studies have produced promising results, showing that the therapy may have a positive effect on motor function and muscle strength. A clinical trial (NCT03056144) to investigate the safety and feasibility of WBVT in children with SMA was terminated when all participants opted to move to a pharmacological intervention trial.

Myostatin inhibition

Myostatin is a protein that occurs naturally in muscles and restrains their growth so they do not grow too large. Therefore, myostatin inhibition may increase muscle strength and function. In a mouse model of mild SMA, myostatin inhibition has been shown to improve muscle weight.

Research has also shown that treatment with recombinant follistatin — a protein that blocks myostatin — improves motor function in a mouse model of severe SMA, while in a mouse model of mild SMA, the injection of a harmless virus carrying the gene providing instructions for follistatin into the muscle of the animals increased muscle weight.

Fast skeletal troponin complex activation

Fast skeletal troponin activators (FSTAs) are molecules that bind selectively to the regulatory troponin complex, a group of proteins involved in muscle contraction. This protein complex is located in the fast skeletal muscles, which contract more quickly to increase their sensitivity to calcium and contractility. Inhibiting this complex increases muscle response, muscle force, and muscle power.

In SMA, it is hoped that FSTAs will increase muscle response despite reduced motor neuron signaling by slowing the release of calcium from the troponin complex in the fast skeletal muscles. 

An FSTA called reldesemtiv was developed by Cytokinetics in collaboration with Astellas Pharma and tested in a placebo-controlled Phase 2 clinical trial (NCT02644668) in patients with SMA types 2, 3, and 4. The results of the trial showed a statistically significant increase in aerobic capacity and endurance in patients treated with reldesemtiv. Patients’ respiratory muscle strength was also increased. Adverse events were similar between groups receiving reldesemtiv and placebo. 

Cholinesterase inhibition

Another approach that may enhance muscle function is treatment with anticholinesterase medications, which inhibit the cholinesterase enzyme and enhance communication between nerves and muscles. Acetylcholine is a neurotransmitter, or cell signaling molecule, released by the neurons to stimulate the muscles. Cholinesterase is an enzyme that breaks down acetylcholine, so a therapy with anticholinesterase medications may enhance muscle contraction and strength.

Mestinon (pyridostigmine bromide) is an anticholinesterase medication being studied in a Phase 2 trial (NCT02227823) in patients with SMA type 3. Another Phase 2 trial (NCT02941328) evaluating the effect of Mestinon versus a placebo in patients with SMA types 2, 3 and 4 has been completed. The trial’s design was described in a study published in BMJ Open.

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