NDC-1308 induces remyelination in models of multiple sclerosis

(10/09/13)

Scientists from ENDECE Neural presented pre-clinical data this week showing that the company's lead compound, NDC-1308, can address one of the root causes of multiple sclerosis (MS) by inducing remyelination (restoration of the lost myelin sheath in nerves that have been damaged by MS). The results, which were presented at the CNS Diseases World Summit 2013 in Boston, suggest that NDC-1308 can induce remyelination in an animal model of demyelination, in which the neurotoxicant cuprizone was used to remove the myelin sheath from the axons (nerve fibers) of mice.



According to the researchers, NDC-1308 induces differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (cells that synthesize and maintain the myelin sheath that covers nerves in the brain and spinal cord).



"For decades, researchers have been seeking ways to induce remyelination in diseases such as MS that are characterized by demyelination," noted James G. Yarger, Ph.D., chief executive officer and co-founder of ENDECE Neural. "Observations that pregnant women typically do not experience the symptoms of MS during the third trimester have led researchers to investigate various forms of synthetic estrogen for the treatment of MS. Our research shows that the estradiol analog NDC-1308 can induce remyelination in demyelinated axons in a cuprizone animal model of demyelination."



In their poster presentation, Dr. Yarger and colleagues described how they synthesized more than 40 proprietary estradiol analogs in which the core structure of estradiol had been modified, and assessed how those modifications changed the hormone's biological activity. NDC-1308 was identified as the most potent of several proprietary analogs having the ability to directly induce differentiation of OPCs into mature oligodendrocytes. By contrast, the female hormones estradiol and estriol do not exhibit that activity. The investigators reported the following findings:



-- In a cuprizone mouse model of demyelination, a 2-week course of NDC-1308 (50 mg/Kg once daily) was associated with a 20% increase in remyelination of hippocampal regions of the brain (P<0.01) in proof-of-concept studies.



-- Consistent with the mouse cuprizone data, NDC-1308 enhanced remyelination in demyelinated rat brain slices in culture visualized by staining for myelin basic protein.



-- NDC-1308 induced isolated OPCs to differentiate into mature oligodendrocytes in culture, whereas estriol and estradiol did not (P<0.01).



-- NDC-1308 caused a dramatic upregulation of genes (5- to 75-fold) in signaling pathways involved in OPC differentiation and myelin sheath production.



"While NDC-1308 is structurally similar to estradiol and estriol, it differs from those two female hormones in that it potently promotes remyelination by inducing OPC differentiation and maturation of oligodendrocytes at the sites of demyelination," explained co-investigator Bruce D. Trapp, Ph.D., who is chair of the Department of Neurosciences at the Lerner Research Institute at the Cleveland Clinic. "NDC-1308 induces significant remyelination of axons in the demyelination model in mice."



"There is a large market opportunity for NDC-1308, as no commercially available drug is capable of directly restoring the lost myelin sheath on damaged axons in patients with MS," added Dr. Yarger. "Dependent on the outcome of clinical studies, we envision NDC-1308 being administered either alone or in combination with current therapeutics that target the immune response and/or inflammation associated with MS. By inducing remyelination, it may be possible to restore muscle control, mobility, and cognition in patients with MS. Therefore, a drug that induces remyelination, such as NDC-1308, could potentially double the size of the current market for MS therapeutics.