Cellular activity is controlled by complex communication processes called signaling pathways, or signal transduction cascades. A signaling pathway is comprised of many proteins and intermediary molecules that work together to carry out biochemical functions such as growth, repair, and metabolism.

Muscular dystrophy is a group of inherited diseases that lead to progressive muscle weakness and loss. One treatment for muscular dystrophy involves using several small molecules that can easily enter the cell and directly act on the signaling pathways, either upregulating them or inhibiting them.

What is signaling pathway inhibition?

Signaling pathway inhibition is the opposite of signaling pathway upregulation. In this process, small molecules called signal transduction inhibitors block the communication between different molecules of the pathway. These signals control many cellular processes, including growth, cell division, and death.

Signaling pathway inhibition can occur either at the protein level or at the gene level.

Signaling pathway inhibitors for the treatment of muscular dystrophy

There are several small molecules that can inhibit the function of specific proteins in signaling pathways. These mitigate disease symptoms in muscular dystrophy, and are summarized below.

Edasalonexent

Edasalonexent is an oral small molecule therapy that inhibits, or blocks, a protein called NF-kappa B in the NF-kappa B pathway. In people with Duchenne muscular dystrophy (DMD), this pathway is active from childhood and is responsible for muscle fiber breakdown and the inability to repair muscle injuries. Therefore, blocking this pathway using edasalonexent can slow muscle fiber breakdown in DMD patients. 

Animal studies have shown that the administration of edasalonexent promotes muscle regeneration and function, especially in skeletal muscles and in the diaphragm and heart.

Phase 1/2 clinical trials have shown good tolerability of edasalonexent in people with DMD. Enrollments are currently open for a Phase 3 multi-center trial further testing the treatment.

Pamrevlumab (FG-3019)

Pamrevlumab (FG-3019) is a human monoclonal antibody that inhibits the function of a protein called connective tissue growth factor (CGTF). CGTF is a pro-inflammatory protein that is necessary for wound healing. Pamrevlumab also can contribute to muscle fibrosis, or the formation of excessive connective tissue in muscles.  It binds to CGTF and blocks its function.

Developed by FibroGen, the therapy was shown to be well-tolerated in a Phase 2 clinical trial with DMD patients. The treatment showed perceivable improvements in respiratory and heart muscle function, and upper arm function.

 

Last updated: July 29, 2019

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