Myelin Regeneration

Myelin Regeneration

One of the markers of Multiple Sclerosis is a form of nerve damage that affects the myelin sheath, or the protective covering over the “tail” of a nerve. When the myelin sheath is damaged (in a process called demyelination), messages that are relayed between nerves and between the body and the brain end up slowing down or even stopping, which leads to neurological problems.

In 1979, Researchers Prineas and Connel showed that in early in Multiple Sclerosis, demyelination is followed by partial or complete remyelination of lesions (damaged tissue). But as the disease runs its course, there is less and less significant remyelination (or healing).

A damaged myelin sheath ends up destabilizing the  axon (tail) of a nerve cell and results in secondary and irreversible neurodegeneration. That’s why identifying the molecular basis for the failure of remyelination and creating drugs to target these pathways is the single most important unmet need in MS.

Why does remyelination fail in MS?

The tissue microenvironment controls the fate of a cell. It also controls the cell’s survival, differentiation, and — importantly — how the cell responds to tissue injury.

When tissue is injured during pathologic processes, profound changes occur in the molecular landscape. This includes:

  1. The release of molecules from injured cells, and
  2. The enzymatic cleavage or chemical modification of the extracellular matrix (ECM) and other extracellular components. (The ECM is a collection of molecules secreted by cells that provides structural and biochemical support to surrounding cells).

 

In both cases, novel molecular motifs previously absent from the tissue microenvironment become abundant.  Within this vast array of new molecular motifs is a group of molecules that signify danger or damage and are recognized by three families of pattern recognition receptors: 1) Toll-like Receptors (TLRs), 2) NOD Receptors, and 3) RIG Receptors.  TLRs form the largest family of pattern recognition receptors and their function in the CNS continues to emerge.

We propose that danger signaling functions in 4 harmful ways in MS: 1) recruitment of destructive innate immune responses leading to secondary injury of oligodendrocytes, myelin and axons; 2) by sending an instructional signal to premyelinating oligodendrocytes and oligodendrocyte progenitor cells that arrests maturation, thus preventing remyelination; 3) by inducing formation of the astrocytic glial scar that further and irreversibly inhibits regeneration; and 4) by increasing susceptibility of neurons/axons to injury.  These four biologic responses to danger signals compromises the natural and inherent myelin repair process in the CNS as well as promoting further injury.

Having identified this dominant pathway that functions to limit normal healthy remyelination, we then developed a bioassay to screen drugs for their ability to promote myelin repair.

“…identifying the molecular basis for the failure of remyelination and creating drugs to target these pathways is the single most important unmet need in MS.”

Most current methods used by other labs to identify drugs that may promote remyelination focus on two main effect of the drugs. They look at:

  • the effect the drugs have on promoting differentiation of oligodendrocytes from oligodendrocyte progenitor cells, or
  • inducing the expression of certain myelin proteins in isolated oligodendrocytes.

 

The advantages of the screens performed in other labs is that that they identify drugs that will enhance normal development of oligodendrocytes and potentially enhance normal myelination.

But in our opinion, the drawback of this approach is that it does not take into account that the environment of the MS lesion is loaded with inhibitors of remyelination. The means that any positive effect could end up being canceled out by the lesion’s environment. Thus, enhancing normal oligodendrocyte development does not necessarily translate into promoting remyelination… if it is within the hostile environment of an MS lesion.

A New Approach

In our lab’s approach to this specific problem, we developed a novel bioassay using mouse cerebellar explants in which:

  1. the normal cytoarchetecture of the CNS is preserved,
  2. a demyelinating insult is applied, and
  3. myelin repair is studied within the context of known inhibitors of remyelination that exist in MS lesions.

 

With regards to the last point, we’ve focused on identifying the small, environmental molecules that might prevent remyelination. Specifically, we’ve develop an assay to identify antagonists to TLR2/MyD88 signaling, as we see this as the major roadblock to normal, healthy remyelination.

We then tested hits in from this screen for their ability to promote remyelination in the cerebellar explants, which simulate the microenvironment of the MS lesion. We have identified candidates within a library of FDA approved compounds and we are currently testing these to optimize their potential to promote myelin repair.

References

Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2.
Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11555-60. doi: 10.1073/pnas.1006496107.

A clear and present danger: endogenous ligands of Toll-like receptors.
Sloane JA, Blitz D, Margolin Z, Vartanian T.
Neuromolecular Med. 2010 Jun;12(2):149-63. doi: 10.1007/s12017-009-8094-x. Review.

Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals.
Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, Flavell R, Strittmatter SM, Volpe J, Sidman R, Vartanian T.
J Neurosci. 2007 Nov 21;27(47):13033-41.

TLR8: an innate immune receptor in brain, neurons and axons.
Ma Y, Haynes RL, Sidman RL, Vartanian T.
Cell Cycle. 2007 Dec 1;6(23):2859-68. Review.

Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis.
Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lü J, Kosaras B, Sidman RL, Volpe JJ, Vartanian T.
J Cell Biol. 2006 Oct 23;175(2):209-15.

A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia.
Lehnardt S, Henneke P, Lien E, Kasper DL, Volpe JJ, Bechmann I, Nitsch R, Weber JR, Golenbock DT, Vartanian T.
J Immunol. 2006 Jul 1;177(1):583-92.

Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T.
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9.

The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.
Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T.
J Neurosci. 2002 Apr 1;22(7):2478-86.

Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis.
Vartanian T, Li Y, Zhao M, Stefansson K.
Mol Med. 1995 Nov;1(7):732-43