Abstract Details

Title Oligodendrocyte Progenitor Cells Differentiation Induction with MAPK/ERK Inhibitor Fails to Support Repair Processes in the Chronically Demyelinated CNS

Topic Multiple Sclerosis

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 6-007

Objective

We aimed to examine the effect of PD0325901 treatment on the chronically-inflamed CNS, and to further characterize its immunosuppressive properties on different cell populations.

Background Remyelination failure is considered a major obstacle in treating chronic-progressive Multiple Sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need of a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models.

Design/Methods We examined the pathological and clinical effect of PD0325901 in Biozzi mouse EAE model in vivo, as well as its effect on OPCs differentiation and immune function in vitro.

Results Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive EAE with PD0325901 showed no clinical improvement in comparison to control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC.

Conclusions Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Authors/Disclosures
Omri Zveik, MD PRESENTER	Mr. Zveik has nothing to disclose.
Tal Ganz	Ms. Ganz has nothing to disclose.
Nina Fainstein	No disclosure on file
Marva Lachish	No disclosure on file
Ariel Rechtman (Hadassah-Hebrew University Medical Center)	Ariel Rechtman has nothing to disclose.
Lihi Sofer	No disclosure on file
Tamir S. Ben-Hur, MD, PhD (Hadassah Hebrew University Medical Center)	The institution of Dr. Ben-Hur has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MAPI Pharma. The institution of Dr. Ben-Hur has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Kadimastem. The institution of Dr. Ben-Hur has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sipnose. The institution of Dr. Ben-Hur has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regenera Pharma. The institution of Dr. Ben-Hur has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medasense. Dr. Ben-Hur has received stock or an ownership interest from Sipnose. Dr. Ben-Hur has received stock or an ownership interest from Kadimastem. Dr. Ben-Hur has received stock or an ownership interest from MAPI Pharma. Dr. Ben-Hur has received intellectual property interests from a discovery or technology relating to health care.
Adi Vaknin-Dembinsky, MD	No disclosure on file

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