Charcot Marie Tooth (CMT) disorder is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people worldwide.
CMT, also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, comprises a group of disorders that affect peripheral nerves. The peripheral nerves lie outside the brain and spinal cord and supply the muscles and sensory organs in the limbs.
Of the many forms of CMT that exist, CMT1A is the most common. CMT1A is caused by a duplication of the gene encoding the peripheral myelin protein-22 (PMP-22), an integral membrane glycoprotein that comprises an estimated 2-5% of the total myelin proteins in the peripheral nervous system. The gene duplication responsible for the CMT1A peripheral neuropathy causes significant dysmyelination across these peripheral nerves resulting in distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity.
Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath in the peripheral nervous system. Researchers have shown that production of PMP-22 in Schwann cells is regulated by the G-protein coupled receptor GABAB where the GABAB receptor specific agonist baclofen was shown to downregulate the amount of PMP-22 produced in myelin.
ADX71441, a potent, selective, orally available small molecule GABAB receptor positive allosteric modulator, demonstrated positive proof of concept data in a validated pre-clinical model of CMT1A. Nine week oral therapy of ADX71441 in CMT rats downregulated pmp22 mRNA, reduced the amount of hypo-myelinated axons and increased compound muscle action potentials in peripheral nerves when compared to vehicle treated CMT rats. We are currently collaborating with the Charcot Marie Tooth Association to further profile ADX71441 in preclinical models of CMT1A and preparing development plans for a Phase I study in healthy volunteers.