ECTRIMS 2016

A small molecule therapy for MS patients appears to override inhibitors of oligodendrogenesis to induce remyelination. 

Presented by Dr. Steven H. Nye and Dr. James G. Yarger, of ENDECE, LLC, on September 15, 2016 at ECTRIMS 2016 in London, U.K.

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Background:

There is an unmet need for remyelinating therapies to treat multiple sclerosis (MS) patients. NDC-1308 is an analog of estradiol (E2) that harnesses the body’s natural remyelinating system to drive oligodendrogenesis, a process resulting in mature, myelinating oligodendrocytes (OLs) that can repair damaged myelin sheaths. NDC-1308 was previously shown in mouse oligodendrocyte progenitor cell (OPC) cultures to induce a 3-fold increase in OLs compared to vehicle. Structurally related estrogens, E2 and estriol, do not possess this activity. Side-by-side comparison of NDC-1308 and E2 activity, following chronic treatment in the cuprizone mouse model of demyelination, showed only NDC-1308 could significantly repair the myelin sheath (44% increase in hippocampus). NDC-1308 can apparently accomplish this by overriding inhibitors of oligodendrogenesis, such as Lingo-1.

Objectives:

We investigated how NDC-1308 has gained the biological activity to repair demyelinated axons, but lost the deleterious side-effects commonly associated with estrogens.

Methods:

Intracellular pathway activation by NDC-1308 and E2 was compared in human cell lines using real-time qPCR. Potential safety concerns for NDC-1308 were addressed. 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. Mutagenicity (Ames assay) and genotoxicity (micronucleus assay) was assessed. Biomarker development was initiated using human PBMCs.

Results:

While NDC-1308 and E2 are both ER agonists, the remyelinating activity of NDC-1308 can be traced back to its unique ability to significantly up-regulate key genes (OLIG2, DNER, MOG and MBP) for oligodendrogenesis. Real-time qPCR analysis showed these same genes are up-regulated 2-3 fold in human PBMCs treated for 12 hours with NDC-1308, suggesting they could serve as potential therapeutic biomarkers. Unlike E2, NDC-1308 was not found to be estrogenic in the mouse uterotrophic assay. Further testing revealed that NDC-1308 is not mutagenic and not genotoxic. The OPC pool remained intact after 6 weeks of chronic NDC-1308 treatment, demonstrating that it can serve as a renewable source for sustaining oligodendrogenesis.

Conclusion:

NDC-1308 is a potential first-in-class remyelinating therapy that possesses many key qualities needed to effectively treat secondary progress (SPMS) and relapsing-remitting (RRMS) MS patients.

2 Comments

  1. Several questions on this
    1. How is it administered
    2. How long does it last or how often do you have to repeat it?
    3. Once it is FDA approved will you have to travel to have it done ?

    Reply
  2. THANK YOU for joining us in London and for making ECTRIMS 2016 a highly successful congress!

    Reply

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