A recent report and findings published in npj Drug Discovery show that an experimental small molecule called CN045 promoted the maturation of myelin-producing cells and demonstrated remyelination activity in preclinical models of multiple sclerosis (MS).
Identifying a Lead for Remyelination
The compound was identified through a screen of approximately 20,000 central nervous system (CNS)-biased small molecules and subsequently demonstrated activity in both mouse and human oligodendrocyte progenitor cells (OPCs), as well as in a mouse model of chronic demyelination.
According to the report, CN045 is brain-penetrable with low cell toxicity and appears to be an attractive contender that can be improved by further lead optimization to generate a clinical candidate for enhancing remyelination in MS patients.
In MS, immune-mediated damage to myelin can disrupt signaling along nerve fibers and contribute to neurologic symptoms and disability.
Current State of MS Treatment
Current disease-modifying therapies primarily target the inflammatory activity underlying the disease, while approaches designed to directly restore damaged myelin remain an area of investigation.
Because oligodendrocytes are responsible for producing myelin in the central nervous system, researchers developed a phenotypic screening strategy focused on promoting the maturation of OPCs into mature oligodendrocytes.
Senior author Bruce D. Trapp, PhD, chair of the Department of Neurosciences at the Lerner Research Institute at Cleveland Clinic in Ohio, and investigators screened approximately 20,000 small molecules selected for properties favorable to CNS drug development.
Screening and Testing
The initial screen generated 390 positive hits, which were subsequently narrowed through secondary screening and dose-response testing.
CN045 demonstrated an EC50 of 40 nM in the OPC differentiation assay and showed greater activity than T3, which was used as a positive control.
Treatment increased the proportion of mature oligodendrocytes and expression of myelin-associated proteins, including proteolipid protein and myelin basic protein.
Investigators next evaluated whether the compound’s effects could be reproduced using human OPCs.
Cells obtained from 3 surgically resected human brain specimens were treated with CN045 for 14 days.
Compared with vehicle, CN045 significantly increased the proportion of mature O4-positive oligodendrocytes.
Modest Remyelination Observed in Mice
The investigators then evaluated CN045 in a cuprizone/rapamycin mouse model of chronic demyelination.
Following 12 weeks of demyelination, animals received CN045 or vehicle for 6 weeks before they assessed remyelination.
CN045 significantly increased remyelination in the corpus callosum, hippocampus, and cerebral cortex, encompassing both white and gray matter regions.
Despite reaching statistical significance, they characterized the magnitude of the remyelination effect as modest.
Overall, the findings establish CN045 as an early lead for a potential remyelination approach in MS, but the compound remains several steps removed from clinical testing.
Further lead optimization, mechanistic studies, and evaluation in additional models will be needed to determine whether CN045 or a related compound can produce sufficiently robust remyelination to warrant clinical development.
More information on multiple sclerosis can be found on the Wikipedia page about clinical trials related to multiple sclerosis is not available but information about Capricor Therapeutics can be found online.