Mysotatin-related Potential SMA Therapies

Myostatin is a protein that occurs naturally in the muscles. Its major function is to prevent skeletal muscles from growing too large in size.

In animals, a lack of myostatin or treatment with myostatin inhibitors has been shown to be associated with a significant increase in muscle mass. Therefore, myostatin inhibition could be a potential therapy for diseases that involve muscle wasting such as spinal muscular atrophy (SMA).

Myostatin signaling

Myostatin is produced in an inactive form by the muscle cells and released outside the cell. When activated by an enzyme, myostatin binds to its receptor, called ActRIIB, which is present on the surface of the muscle cells. ActRIIB activates a pathway that inhibits the growth of muscle cells through the alteration of gene expression.

Myostatin inhibition

There are many approaches for inhibiting myostatin, the most common being the use of monoclonal antibodies that specifically bind to myostatin and inactivate it. Another approach is the use a protein called follistatin, which occurs naturally in the muscles and functions to block myostatin activity. Myostatin activity could also be inhibited by using specific antibodies against its receptor ActRIIB.

Anti-myostatin antibodies

REGN1033, developed by Regeneron, is a specific and potent anti-myostatin antibody. It was shown to enhance muscle mass and function in young and aged mice. It has also been shown to have beneficial effects in models of skeletal muscle atrophy.

Pfizer is currently testing an anti-myostatin antibody (PF06252616) in a Phase 2 trial (NCT02310763) in Duchenne muscular dystrophy (DMD) patients.

Bristol-Myers Squibb (BMS) is conducting a Phase 2 study in DMD patients (NCT02515669) with anti-myostatin adnectin (BMS-986089), molecules derived from human fibronectin that function in a similar way to antibodies.

Follistatin-mediated inhibition

FS344, an alternatively spliced form of follistatin that exclusively binds to myostatin, has been shown to increase muscle fiber size in Becker muscular dystrophy patients. FS344 is now being tested in patients with DMD (NCT02354781).

Myostatin receptor inhibition

Acceleron was testing the safety and effectiveness of soluble ActRIIB ACE-031 antibody in DMD patients but the clinical trial (NCT01099761) was terminated due to adverse events including nose bleeds and dilated blood vessels. The myostatin receptor ActRIIB is involved in signaling from several molecules besides myostatin, so these toxicities could be due to off-target effects.

Myostatin inhibition in SMA

Researchers have shown that treatment with recombinant follistatin improves motor function in a mouse model of severe SMA, while in a mouse model of intermediate SMA, intramuscular injection of adeno-associated virus serotype 1 (AAV1) encoding for follistatin (FS344) increased muscle weight.

A myostatin inhibitor called apitegromab (SRK-015) is currently being tested in children and young adults with SMA type 2 and type 3. A total of 58 patients ages 2 to 21 are receiving intravenous infusions of apitegromab every four weeks. Interim results after six months of treatment showed that roughly two-thirds of participants had at least a one-point increase in the Revised Hammersmith Scale and the Hammersmith Functional Motor Scale Expanded (HFMSE) and 35% of patients had a three or greater increase in scores.


Last updated: Jan. 3, 2021


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