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The earliest MS lesions are characterized by oligodendrocyte death and demyelination, which in many cases is followed by robust remyelination. Remyelination is carried out by oligodendrocyte progenitor cells (OPCs), which are resident multipotent stem cells in the CNS that are capable of differentiating into mature oligodenrocytes to form myelin. When remyelination occurs it restores salutatory conduction and trophic support to the axon. There are however, differences between myelin internodes that are the product of normal development and those that are made in the process of remyelination. The most notable are that internodes made during remyelination are shorter in length and are composed of fewer wraps of myelin.

As MS lesions evolve over time, the tissue microenvironment becomes modified with an ever-increasing quantity and variety of molecular inhibitors of remyelination. These inhibitors, collectively termed Damage Associated Molecular Patterns (DAMPs), are the products of cell death, inflammatory responses, and leaky CNS blood vessels.

Following oligodendrocyte death and demyelination, intracellular contents are spilled into the extracellular environment and many of these molecules such as HMGB1 are known DAMPs. The products of cell death are immediately deposited into the tissue microenvironment of the new lesion. This results in partial or temporary inhibition of remyelination.

As resident innate immunity is activated and infiltrating innate and adaptive immune cells are recruited by the initial cell death and demyelination, products of inflammation including: reactive oxygen and reactive nitrogen species, enzymatic modifications of the extracellular matrix and cell membranes, and a host of other process result in production of new DAMPs and lasting molecular changes in the tissue microenvironment. This process is compounded by the activation of astrocytes that synthesize and modify much of the CNS extracellular matrix leading to the beginning of glial scar formation.

As time progresses and lesions become reactivated or chronically activated, this process of DAMP production continues and the lesion landscape has an ever increasing and complicated molecular architecture that inhibits remyelination.

DAMPs inhibit remyelination by interacting with OPCs and preventing them from differentiating into mature oligodendrocytes, a necessary step for remyeination to occur. A major mechanism by which DAMPs block OPCs from developing into mature myelinating oligodencrocytes is through activation of pattern recognition receptors on OPCs, principally Toll-Like Receptor 2 (TLR2).

Some of the DAMPs that function to inhibit remyelination are known. Low molecular weight hyaluronan generated by the enzymatic cleavage of hyaluronic acid, the principle extracellular matrix component of the CNS, is a potent inhibitor of remyelination through activation of the TLR2/MyD88 pathway in oligodendrocyte progenitor cells (OPCs). Chondriotin Sulfate Proteoglycan (CSPG) is another extracellular matrix component known to prevent remyelination and is a known TLR2 agonist.

In addition to their effect on inhibiting the generation of myelinating oligodendrocytes from OPCs, DAMPs also activate innate immunity and astrocytes in the CNS resulting in amplification of an environment hostile to myelin regeneration and axonal health.

Identifying the basic cellular and molecular mechanisms of inhibition of myelin regeneration in MS is the work of several labs around the world. The goal of Neurogen is to seek evidence for the effectiveness of drugs that target these pathways and promote remyelination in preclinical models and in clinical trials.

The problem of myelin regeneration is bigger than any one lab or individual research program. Efforts to solve this problem include understanding the basic mechanisms leading to inhibition of myelin regeneration, creating assays to screen libraries of compound to pull out drugs effective against the relevant inhibitory pathways, testing these potential pro-remyelination drugs in preclinical models of demyelination and remyelination relevant to MS, optimizing drugs that work in these preclinical assays through traditional and theoretical medicinal chemistry, a mechanism t decide which drugs should be moved forward for human study, a highly specific and quantitative method for detecting remyelination in humans with MS non-invasively, post-processing and statistical analysis to generate unbiased interpretation of the results.

Neurogen’s goal is to foster the best work in preclinical and clinical testing of potential remyelinating drugs. In doing so, we have created a network of highly collaborative scientists and clinicians who have expertise in myelin imaging in preclinical models, drug discovery, preclinical models of remyelination, advanced MRI imaging techniques for assessing remyelination in people with MS, clinical research logistics and biostatistics.