Oligodendrogenesis Via a Small Molecule Therapy for Treating Multiple Sclerosis Patients

Background: There is an unmet need for remyelinating therapies for diseases like multiple sclerosis (MS). Remyelination depends upon the ability of endogenous oligodendrocyte progenitor cells (OPCs) to differentiate into mature oligodendrocytes that can then repair the damaged myelin sheath. NDC-1308 is an analog of estradiol (E2) that was previously shown in culture to cause 3-fold more mouse OPCs to differentiate into mature myelinating oligodendrocytes compared to vehicle. E2 and estriol do not possess this myelinating activity. Side-by-side comparison of NDC-1308 and E2 in the cuprizone mouse model of demyelination showed that only NDC-1308 dramatically increases the level of remyelination (up to 44% in the hippocampus). 

Objectives: We investigated how NDC-1308 has gained the function to remyelinate axons, but lost the deleterious side-effects commonly associated with estrogens.  

Methods: In silico modeling was used to compare the orientation of NDC-1308 in the estrogen receptor (ER) ligand binding domain to E2. The affinity of NDC-1308 for different ER subtypes was characterized using a fluorescence polarization-based assay. Intracellular pathway activation of NDC-1308 was compared to E2 by real-time qPCR in several human cell lines.  We determined whether NDC-1308 is estrogenic, a potential safety concern for treating MS patients. Estrogenicity was directly measured in a mouse uterotrophic assay since E2 treatment is known to cause a rapid and dramatic increase in uterine weight in this assay. 

Results: In silico modeling studies suggest that NDC-1308 interacts with different moieties in the ER ligand binding domain compared to E2, thereby eliciting a distinct pattern of gene expression that is beneficial for myelin repair. Indeed, while NDC-1308 and E2 are both ER agonists, the unique remyelinating activity of NDC-1308 can be traced back to its ability to significantly up-regulate key genes (OLIG2, DNER, MOG and MBP) for oligodendrogenesis and remyelination. Real-time qPCR analysis showed these same genes are up-regulated in human PBMCs treated with NDC-1308, suggesting they could serve as potential therapeutic biomarkers. Unlike E2, NDC-1308 was not found to be estrogenic in the uterotrophic assay. Further testing revealed that NDC-1308 is not mutagenic and not genotoxic. 

Conclusions: Because of its unique mechanism of action, its potent remyelinating activity and its demonstrated lack of harmful side-effects, NDC-1308 possesses many desirable attributes of an effective MS therapy.