Abstract Details

Title Specific Blockade of Bone Morphogenetic Protein-2/4 induces Oligodendrogenesis and Remyelination in Demyelinating Disorders

Topic Multiple Sclerosis

Presentation(s) S11 - MS Immunology and Basic Science (4:24 PM-4:32 PM)

Poster/Presentation
Number 003

Objective To investigate the effect of BMP2/4 blockade on remyelination and oligodendrocytes regeneration in animal models of demyelination.

Background Oligodendrocyte precursor cells (OPCs) are present in demyelinated lesions of multiple sclerosis (MS). However, their differentiation into functional oligodendrocytes is insufficient, and most lesions evolve into nonfunctional astroglial scars. Blockade of bone morphogenetic protein (BMP) signaling was found to induce differentiation of OPCs into myelin-producing oligodendrocytes.

Design/Methods We studied the effect of specific blockade of BMP-2/4 signaling, by intravenous (IV) treatment with anti-BMP-2/4 neutralizing mAb or a noval small molecule (SM) that was found to block BMP2/4 signaling in both the inflammatory model of relapsing experimental autoimmune encephalomyelitis (R-EAE) and the cuprizone- a toxic model of demyelination in mice. We analyzed the clinical, histopathological and electron microscopic data.

Results Administration of either anti-BMP-2/4 mAb or SM to R-EAE- induced mice similarly ameliorated R-EAE symptoms, diminished the expression of phospho-SMAD1/5/8, increased the numbers of de novo pro-oligodendrocytes and mature oligodendrocytes, and reduced the numbers of newly generated astrocytes within the spinal cord. This effect was accompanied with elevated remyelination, manifested by increased density of axons with g-ratios above 0.8, and reduced fully demyelinated and demyelinating axons in the anti- BMP-2/4- treated R-EAE mice demonstrated by electron microscopy. Moreover, IV treatment with anti-BMP-2/4 mAb or SM in the cuprizone-challenged mice augmented the numbers of mature oligodendrocytes and remyelination in the corpus callosum during the recovery phase of the disease. Pharmacokinetic study of the SM found a T1/2 of 6 hours for both IP and oral administration andIC50 of 1.54uM. The oral bioavailability was 68.6%.

Conclusions Based on our findings, specific blockade of BMP-2/4 mAb or SM has therapeutic potential in demyelinating disorders such as MS, by inducing oligodendrogenesis- mediated remyelination in the affected tissue. There is still a need to decide on the preferred route of treatment administration.

Authors/Disclosures
Arnon Karni, MD, PhD (Tel Aviv Sourasky medical center) PRESENTER	Prof. Karni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neopharm. Prof. Karni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. Prof. Karni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Prof. Karni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Prof. Karni has received research support from Medison. The institution of Prof. Karni has received research support from BMS. The institution of Prof. Karni has received research support from Novartis.
	No disclosure on file
Moshe Benhamou (Tel Aviv University)	No disclosure on file
Maya Golan	No disclosure on file
Nadav Bleich Kimelman	Nadav Bleich Kimelman has nothing to disclose.
Uri Danon	Uri Danon has received personal compensation for serving as an employee of Mapi harma.
Ehud Marom	Mr. Marom has received personal compensation for serving as an employee of Mapi Pharma. Mr. Marom has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Mapi Pharma. Mr. Marom has stock in Mapi Pharma. Mr. Marom has received intellectual property interests from a discovery or technology relating to health care.

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