Spinal muscular dystrophy (SMA) is caused by an inherited genetic mutation in the SMN1 gene, which encodes for the survival of motor neuron (SMN) protein in motor neurons. A lack of SMN protein results in impaired neuronal function and subsequent impaired muscular function.

In addition to drugs that aim to upregulate the expression of the SMN protein, a potential therapy for SMA patients could be directly targeting the muscle to improve their function. The most promising approaches include exercises and physiotherapy, myostatin inhibition, activation of androgen receptors, activation of fast troponin complexes, blocking of TWEAK signaling, targeting mitochondrial dysfunction, and cholinesterase enzyme inhibition.

Exercise and physiotherapy

In a mouse model with mild SMA, long-term exercise (running and swimming) was shown to significantly improve motor performance (grip strength), motor neuron survival, muscle resistance to damage, and neuromuscular junction structure.

An innovative physiotherapeutic approach, based on physical training in a swimming pool, is currently under a pilot study (NCT02061189) to assess improvements in motor function.

More studies are needed to understand the mechanisms underlying exercise-induced benefits in SMA patients.

Whole body vibration therapy (WBVT) has been suggested to have beneficial effects on muscle function in healthy adults and post-menopausal women. There have also been studies on WBVT for children with muscular dystrophies that have shown promising results on motor function and muscle strength and the approach appears to be safe in children with SMA. A clinical trial (NCT03056144), which is not yet open for participant recruitment, will investigate the safety and feasibility of WBVT in children with SMA.

Myostatin inhibition

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

Androgen receptor activation

Another approach to increase muscle size is activating androgen receptors with selective androgen receptor modulators (SARMs). These are tissue-specific compounds that stimulate muscle growth and improve muscle function. Many SARMs have been developed for diseases associated with muscle wasting and their potential in SMA has to be clarified.

Fast-troponin complex activation

Fast skeletal troponin activators (FSTAs) are molecules that bind selectively to the troponin protein in the fast skeletal muscle (a type of skeletal muscle that contracts at a faster speed) to increase its sensitivity to calcium. This results in increased muscle response, muscle force, and power, but decreases the activity-induced fatigue.

One such FSTA called CK-2127107, developed by Cytokinetics in collaboration with Astellas Pharma, is currently the focus of a Phase 2 clinical trial (NCT02644668) in patients with SMA types 2, 3 and 4. It aims to increase muscle response despite reduced motor neuron signaling by slowing the release of calcium from the troponin complex in the fast skeletal muscle.

TWEAK signaling blockade

TWEAK is a protein that binds to muscle fibers and leads to muscle protein degradation, impaired differentiation, changes in muscle oxidative metabolism, and muscle atrophy. Research has shown that blocking the TWEAK protein with anti-TWEAK antibodies increases muscle mass, improves muscle metabolism and function, reduces muscle degeneration, and promotes muscle regeneration in mice. However, the muscle-protective role of this approach in SMA has not been studied.

Mitochondrial function

Signs of mitochondrial dysfunction have been observed in SMA muscles, including a decrease in mitochondrial proliferation, content, and function. Olesoxime is a neuroprotective drug that binds to the mitochondrial permeability pore, which is involved in oxidative stress and metabolite uptake. It is currently under study in a Phase 2 clinical trial (NCT02628743) by Roche to study its effectiveness in improving motor function in SMA patients.

Cholinesterase enzyme inhibition

Another approach that may enhance muscle function is treatment with anti-cholinesterase drugs, which inhibit the cholinesterase enzyme and enhance communication between nerves and muscles. Acetylcholine is a neurotransmitter released by the neurons to stimulate the muscles. Cholinesterase is an enzyme that breaks down acethylcholine, so a therapy with anti-cholinesterase drugs may enhance muscle contraction and strength. Mestinon (pyridostigmine bromide), an anti-cholinesterase drug, is being studied in a Phase 2 clinical trial (NCT02227823) in SMA type 3 patients. Another Phase 2 trial (NCT02941328) evaluating the effect of Mestinon vs. placebo in patients with SMA types 2, 3 and 4 is currently recruiting participants in the Netherlands.

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