Small Molecule Therapies

Muscular dystrophy is the name given to a group of inherited diseases characterized by progressive muscle weakness and wasting. Current therapies can help manage the symptoms of the disease, and slow down its progression, but cannot cure it. However, there are several experimental treatments — such as small molecule therapies — that are being investigated and have the potential to vastly improve the symptoms.

Small molecules are compounds with low molecular weights that can easily enter cells and directly affect the target, which may be a protein or other molecules within the cell. More than 90% of the therapeutics made today are small molecules.

Some of the small molecules being studied as potential muscular dystrophy therapies are summarized below, grouped by their mechanism of action.

Signaling pathway upregulation

Signaling pathway upregulation is a means of increasing the availability of cellular molecules — such as proteins, mRNA, or even energy — via an external agent such as a small molecule.

Puldysa (idebenone) is a synthetic analog of ubiquinone (co-enzyme Q10), which is a key component of an energy pathway in the mitochondria, called the electron transport chain. Puldysa helps increase energy production inside cells, as well as protect them from damage.

Oxandrolone is a synthetic equivalent of testosterone. It works by mimicking the function of the male hormone testosterone, and upregulates the synthesis of many proteins required for proper muscle growth and function.

Signaling pathway inhibition

Contrary to upregulation, signaling pathway inhibition is a method of decreasing the end result of certain biochemical mechanisms in the cell. It blocks the functioning of proteins or genes via small molecule inhibitors.

Edasalonexent is a small molecule that inhibits a protein called NF-kappa B in the NF-kappa B pathway. This pathway is activated in people with Duchenne muscular dystrophy (DMD), resulting in muscle fiber breakdown and the inability to repair muscle injuries. 

Pamrevlumab (FG-3019) is an antibody that binds to, and inhibits, the function of connective tissue growth factor (CGTF). CGTF is a pro-inflammatory protein that can lead to muscle fibrosis — formation of excessive connective tissue.

Myostatin inhibition

Myostatin inhibition is a well-known method of promoting muscle growth. Small molecules such as RG6206 (talditercept alpha) and Domagrozumab (PF-06252616) inhibit myostatin and help increase muscle mass in people with DMD. RG6206 is currently being investigated in various ongoing clinical trials, but Domagrozumab has been discontinued due to unsatisfactory results. ACE-083 is another activin and myostatin inhibitor currently being studied for the treatment of facioscapulohumeral muscular dystrophy (FSHD).

Utrophin upregulation

Utrophin upregulation is an actively researched therapeutic approach for the treatment of DMD. Utrophin is similar to dystrophin, but is produced only during embryonic development. It is hypothesized that increased utrophin during adulthood can compensate for the lack of dystrophin in DMD patients. Ezutromid and TVN-102 upregulate the production of utrophin to substitute for the deficiency of dystrophin in people with DMD. While the development of Ezutromid is now terminated, TVN-102 was shown to have good efficacy in pre-clinical studies.

Another utrophin upregulation therapy being investigated is rhLAM-111. rhLAM-111 is a recombinant human laminin 111 protein that promotes the production of utrophin and another cell adhesion protein called alpha7beta1 integrin. This can stimulate muscle regeneration and improved muscle cell adhesion.

Immune system modulation

Immune system modulation, also called as immunomodulation, is the process of altering the activity of the immune system, often to reduce tissue damage.

Resolaris (ATYR1940) is an intravenous protein therapy that works on the resokine pathway to modulate the immune system and reduce muscle tissue damage in FSHD and limb-girdle muscular dystrophy 2B (LGMD2B).

MNK-1411 is the synthetic equivalent of the adrenocorticotropic hormone. It is a synthetic melanocortin agonist — a substance that acts like another substance, stimulating an action — that acts on melanocortin receptors. It delays the progression of DMD by modulating immune system activity and reducing muscle inflammation.


Last updated: 07/18/2019


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