Myelin is critical to the normal functioning of the Central Nervous System (CNS). By serving as an insulator, myelin facilitates rapid conduction of electrical impulses along axons in the brain and spinal cord, transmitting neuronal signals to and from muscles, sensory organs and cognitive centers. When myelin is damaged in Multiple Sclerosis (MS), conduction of impulses along axons slows or stops altogether, which leads to the various neurologic symptoms that people with MS experience. Myelin is also essential to maintain the structural integrity and health of axons. The relationship between myelin and axons appears symbiotic - that is, in the absence of axons, myelin degenerates, and in the absence of myelin, axons degenerate. Thus, the implications of myelin loss in MS are devastating because not only is impulse conduction along axons impaired, but axons also suffer irreversible degeneration after sustained demyelination. Consequently, regeneration of myelin in MS is vital.
Why does myelin fail to repair or regenerate itself in multiple sclerosis? A certain degree of myelin regeneration commonly occurs in MS following demyelination. However, over time, this normal regenerative capacity is lost, and cumulative demyelination leads to secondary axonal degeneration. These are the hallmarks of progressive disability in MS.
If myelin can regenerate to some degree, why does myelin regeneration ultimately fail in MS? Biologic processes, such as myelination, are regulated by a balance of “on” and “off” signals. Regeneration of myelin in multiple sclerosis appears to be primarily blocked by the presence of “off", or inhibitory, signals. During the process of inflammatory demyelination in MS, molecules are released that are termed “danger signals”. These danger signals alert cells that the local environment is hostile and not suitable for growth.
One of the most abundant and important danger signals in MS lesions is hyaluronic acid, or hyaluronan. Hyaluronan is a large linear molecule that normally functions as part of the scaffolding outside of cells, the extracellular matrix. In MS lesions, as part of inflammatory response, hyaluronan is broken down into smaller fragments, and these small or low molecular weight hyaluronan fragments function as danger signals that activate a specific receptor, toll-like receptor 2 (TLR2) on oligodendrocytes. Oligodendrocytes are the myelin generating cells in the CNS. Hyaluronan and other danger signals that activate TLR2 on oligodendrocytes prevent them from making myelin. In the presence of hyaluronan fragments, oligodendrocytes do not die, but rather are held in a kind of suspended animation, unable to make the myelin necessary for axonal function and health.
This effect is consistent with the observation that within MS lesions there are abundant numbers of oligodendrocytes adjacent to axons but they fail to form myelin.
The goal of the Myelin Regeneration Project is the development of compounds for Phase I clinical studies that demonstrate functional activity in myelin regeneration. All relevant targets for drugs, such as the hyaluronan-TLR2 pathway, will undergo rigorous analysis for development of high throughput assays to screen compounds ultimately suitable for clinical investigation.
Goals and Strategy
The Myelin Regeneration Project is a focused effort to deliver drugs suitable for Phase I clinical investigation that have demonstrated activity in myelin regeneration assays, based on the NIH Blueprint for Therapeutic Development.
- Target identification
- Primary screening assay
- Secondary confirmation assay
- Selectivity and specificity screening assay
- Medicinal chemistry optimization
- Investigational new-drug-directed toxicology and pharmacology
The importance of regenerative compounds in MS therapeutics cannot be overestimated. Disability progression is observed in most patients on FDA-approved therapeutics, and restoring myelin to demyelinated axons serves to improve the function of those axons. More importantly, this restoration prevents the inevitable degeneration that occurs when axons are chronically demyelinated. Myelin regeneration represents the largest unmet need in MS therapeutics.