Contributions
Abstract: P1280
Type: Poster
Abstract Category: Therapy - disease modifying - Treatment of progressive MS
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.
Disclosure: Steven Nye is an employee and shareholder of ENDECE.
James Yarger is an employee and shareholder of ENDECE.
Abstract: P1280
Type: Poster
Abstract Category: Therapy - disease modifying - Treatment of progressive MS
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.
Disclosure: Steven Nye is an employee and shareholder of ENDECE.
James Yarger is an employee and shareholder of ENDECE.