How does ricolinostat work?
CMT is characterized by peripheral neuropathy, or damage to the nerves that carry messages between the brain and spinal cord and the rest of the body. This damage leads to weakness, numbness, and pain in the hands, feet, arms, and legs.
Nerve cells in the peripheral nervous system often have axons, or extensions, that cover long distances. Most cellular components are manufactured close to the body of the cell, near the nucleus. Proteins, as they are made, need to be transported from their manufacturing center near the nucleus to a cell’s far reaches. Because the axons of peripheral nerves are so long, this transport is especially challenging. Vesicles (a type of small “shipping” compartment) and proteins travel along a cellular “railway” made up of tubulin proteins woven together like fibers to make a thick, more stable transit path.
In at least some cases of CMT, the disease may be caused by the destabilization of this tubulin supply network. A particular chemical modification called acetylation changes the way tubulin folds, so that the fibers stick to each other instead of existing as individual subunits; the loss of the chemical modification makes the tubulin proteins unstable, and the network falls apart. Without the supply network, vesicles cannot get to the far reaches of a cell’s axon, and nerve cells cannot work properly.
Ricolinostat is a small molecule that inhibits an enzyme called histone deacetylase 6 (HDAC6), which removes acetyl groups from proteins. By blocking this enzyme, the acetylation on tubulin remains and stabilizes the supply network in the nerve. If the supply network is stable, the neuropathy caused by CMT may ease or end altogether.
Ricolinostat in clinical trials
Ricolinostat has been shown to be safe and well-tolerated in Phase 1 and Phase 2 clinical trials involving healthy volunteers.
Regenacy has announced that it is planning to begin Phase 2 clinical trials of ricolinostat in treating peripheral neuropathy caused by CMT. The company, however, has not published updated data on this potential therapy since 2018.
Last updated: Feb. 26, 2020
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