Remyelination in MS: Recent Developments

Hard on the heels of the first biological evidence of repair of damaged myelin in the human brain, presented at the recent American Academy of Neurology meeting, several new studies also feature developments in remyelination in multiple sclerosis (MS). These include potential therapeutics that may promote remyelination. Also, oligodendrocyte precursor cells appear to be a promising target for MS treatments, and microRNA expression may be an attractive biomarker in MS.

Turn the pages to learn more about these studies.

Targeting Oligodendrocyte Precursor Cells

♦ MS is a progressive demyelinating disease of the central nervous system (CNS).

♦ Demyelination of nerve axons removes metabolic support, leading to irreversible neurodegeneration.

♦ Leukemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in immunity, has recently been identified as a pro-myelination factor.

Targeted LIF Increased Remyelination

♦ Targeted delivery of LIF to oligodendrocyte precursor cells may promote differentiation into mature oligodendrocytes able to repair myelin.

♦ Using an in vivo model of CNS demyelination, these researchers showed targeted LIF increased the number of myelinated axons and the thickness of myelin per axon.

♦ A single nanoparticle dose delivering picomolar quantities of LIF was sufficient to increase remyelination.

New Era of MS Drug Delivery

♦ This experiment paves the way for a new era in therapeutic delivery of drugs or biologics targeted to potently enhance CNS remyelination in MS patients.

♦ Combinations of drugs and biologics may even be co-encapsulated within the same nanoparticle for either simultaneous or sequential delivery.

Source: Rittchen S, et al. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF). Biomaterials. 2015 July: 78–85.

Drug-based Modulation of Endogenous Stem Cells

♦ Prevention of neural degeneration and subsequent disability in MS requires remyelination through the generation of new oligodendrocytes.

♦ Oligodendrocyte progenitor cells are stem cells in the CNS and the principal source of myelinating oligodendrocytes.

♦ These cells are abundant in demyelinated regions of MS patients, and therefore are a cellular target for pharmacological intervention.

2 Drugs Increased Oligodendrocytes and Enhanced Myelination

♦ These researchers found 7 drugs selectively enhanced the generation of mature oligodendrocytes from progenitor cells in vitro.

♦ The antifungal agent miconazole and the corticosteroid clobetasol effectively promoted myelination in early postnatal mouse pups.

♦ Systemic delivery of each of the 2 drugs significantly increased the number of new oligodendrocytes and enhanced remyelination in a mouse model of focal demyelination.

Further Testing of Micronazole and Clobetasol Warranted

♦ Mechanistic studies show that miconazole functions through mitogen-activated protein kinase and clobetasol functions through glucocorticoid receptor signaling.

♦ Both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro.

♦ These results provide a rationale for testing miconazole and clobetasol to enhance remyelination in MS patients.

Source: Najm FJ, et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature. Published online 20 April 2015.

MicroRNA Expression Reduced in MS Patients

♦ MicroRNA 572, which is deregulated in MS, may be a target of neural cell adhesion molecule, a glycoprotein involved in CNS repair mechanisms.

♦ These researchers isolated microRNA 572 from serum in 62 MS patients, 16 with primary progressive disease, 15 with secondary progressive disease, and 31 with relapsing remitting disease, and 15 sex- and age-matched healthy controls.

♦ MicroRNA 572 expression was reduced overall in MS patients as compared to controls.

MicroRNA 572 May Serve as Biomarker for Remyelination

♦ This microRNA was significantly upregulated in secondary progressive MS and in relapsing remitting MS during disease relapse. It was downregulated in primary progressive MS and in quiescent phases of relapsing remitting MS.

♦ The researchers believe that microRNA 572 might be a tool to distinguish between primary progressive MS and secondary progressive MS and between relapsing and remitting phases in relapsing remitting MS.

♦ Evaluation of this microRNA may serve as a non-invasive biomarker for remyelination.

Source: Mancuso R, et al. MicroRNA-572 expression in multiple sclerosis patients with different patterns of clinical progression. J Transl Med. 2015 May 7;13:148.

Remyelination Is Attractive Treatment Strategy

♦ MS is characterized by inflammatory demyelinating lesions and axonal loss.

♦ Promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy.

♦ One of the pathways that may contribute to impaired remyelination in MS lesions is the Wnt/β-catenin pathway.

NSAID Enhances Endogenous Remyelination

♦ The non-steroidal anti-inflammatory drug indomethacin has been shown to modulate the Wnt/β-catenin pathway.

♦ These researchers showed indomethacin promotes differentiation of primary human and murine oligodendrocytes, myelination of cerebellar slice cultures and remyelination in cuprizone-induced demyelination.

♦ Indomethacin may represent a promising treatment to enhance endogenous remyelination in MS patients.

Source: Preisner A, et al. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. Acta Neuropathol. 2015 May 6.

Take Home Points

♦ Researchers discovered several potential remyelination enhancers for MS patients:

            1. Cytokine LIF

            2. Antifungal agent miconazole and corticosteroid clobetasol

            3. NSAID indomethacin

♦ Also, the evaluation of microRNA 572 could become a non-invasive biomarker for remyelination.