NOVO-118 as a therapeutic to promote remyelination in in vivo models of MS

7. Project Summary
Multiple sclerosis (MS) is a neurodegenerative disease in which myelin of the central nervous system (CNS) is
destroyed by a self-reactive immune response. This demyelination is accompanied by the death of the
myelinating cells themselves, the oligodendrocytes. Repeated bouts of demyelination leave the denuded CNS
neurons vulnerable to degradation and is the major cause of neuronal dysfunction and neurodegeneration in
MS. Current approved therapies for MS are aimed only at lessening the frequency of the auto-immune attack
and do not address the need for remyelination. Without induction of remyelination to heal previous lesions, the
course of disease can only be slowed but not reversed.
The CNS contains a large population of oligodendrocyte precursor cells (OPC) that have the potential to
differentiate into mature oligodendrocytes and remyelinate denuded axons. Although OPCs are efficiently
recruited into MS lesions, OPC differentiation into mature oligodendrocytes, and subsequent remyelination, is
inhibited in MS. Novoron has discovered that the LRP1 receptor is a key signaling molecule that prevents OPC
differentiation. By abrogating LRP1 function using either genetic deletion or antagonism, we can increase OPC
differentiation and restore the remyelinating capacity of the brain.
The goal of this proposal is to transition from our preliminary data demonstrating our novel approach to
remyelination to developing this technology into a viable human drug. By the end of this Phase 1 application,
Novoron will possess the following: 1) a lead drug candidate with an in vivo dose-response profile, 2) disease
efficacy data in the cuprizone chemical demyelinating model, and 3) disease efficacy data in the autoimmune-
mediated EAE MS model. These data will demonstrate the feasibility of our approach to healing MS leasions
and preapre Novoron for an efficient comercialization-focused Phase 2 application.8. Project Narrative
Disability and death in multiple sclerosis result from neuronal damage that arises from demyelination.
Oligodendrocyte progenitor cells (OPCs) have the ability to infiltrate areas of demylination and remyelinate
denuded axons, thereby preventing neuronal damage and reversing disability, but their differentiation into
mature myelinating oligodendrocytes is inhibited by debris within the lesion site. The goal of this project is to
further characterize and develop our lead molecule with the objective of creating the first therapeutic to
overcome the suppression of OPC differentiation and restore myelination thereby overcoming the functional
deficits that result from neuronal damage and loss.