Multiple sclerosis: towards regeneration!

Research Published February 28 2017
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Why does multiple sclerosis progress more rapidly in some patients than in others? Why do some patients with multiple sclerosis succeed in repairing demyelination damage over the course of the disease and others not?

A joint study led by ICM researchers Violetta Zujovic (INSERM), Isabelle Rebeix (INSERM) and Bertrand Fontaine (AP-HP, UPMC) published in Brain highlighted the key role played by T-cells in myelin regeneration and opened up new opportunities for cell-based therapy.

Multiple sclerosis (MS) is an inflammatory disease of the nervous central system leading to a progressive destruction of the myelin sheath surrounding axons, essential for their protection and for the transmission of the nerve impulse. Efficient myelin repair is a key factor in fighting against disease progression. Understanding why and how the illness progresses more or less rapidly in certain patients is essential.

Prior studies have shown that in certain patients, when a lesion appears it is immediately repaired whereas it never repairs itself in other patients. T-cells are the main actors in the inflammatory process through myelin destruction, acting as if myelin was a foreign body. Consequently, ICM researchers hypothesized that T-cells, key players in inflammation and myelin destruction, may play a part in remyelination success or failure.

To gain a deeper understanding of the process, ICM researchers (AP-HP, Inserm) grafted T-cells from healthy donors or MS patients in demyelinated spinal cord lesions in mice. Using this new model, they showed that reparative stem/precursor cells are recruited in lesions but do not differentiate into myelin-reparative cells. They highlighted that T-cell activity was enacted through an interaction between macrophages and microglial cells that coordinate repair.

In the case of patients with strong remyelination capacities, T-cells send the appropriate signals to activate repair, leading to cell recruitment and differentiation into myelin-repairing cells. In the case of patients with low remyelination capacities, T-cells do not enable appropriate microglial activation, thereby affecting the entire chain of repair.

 

“The study of T-cells in patients with strong remyelination capacities is a promising approach that may be helpful in developing novel strategies for myelin regeneration. This systematic study could help both for diagnosis and treatment in order to develop precise medical care, tailored to each patient, on the long run,” explain the study’s authors: Violetta Zujovic (INSERM), Isabelle Rebeix (INSERM) and Bertrand Fontaine (AP-HP, UPMC).

 

Researchers compared T-cell secretion profiles in patients with strong or weak remyelination capabilities, and highlighted 3 molecules associated with proper remyelination and 3 molecules associated with a defect in myelin repair.

Among them, molecule CCL19 is associated with weak remyelination capabilities. Researchers hypothesized that deactivating the molecule would allow microglia and macrophages to reach levels enabling the repair of multiple sclerosis lesions.

Results may direct research towards treatments for other pathologies including amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease in which microglia are also essential in lesion repair.

Scientific teams

Team “Gene Therapy”
Team leader
Nathalie CARTIER MD, PhD, DRE, INSERM
Gene therapy Main domain: Clinical & translational neurosciences Subdomain : Molecular & cellular neuroscience Nathalie CARTIER’s team develops gene therapy strategies for severe neurodegenerative diseases including Huntington's disease, Spinocerebellar ataxias, Alzheimer's disease and genetic leukodystrophies. Research includes proof of concept in animal models and translational steps to clinical applications. The team aims to propose a phase I/II therapeutic trial in 2020 for Huntington disease. The team will also develop tools for the delivery of therapeutic molecules in the brain (use of microglia, optimization of AAV for intravenous administration, optogenerapy for time-controlled delivery).
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Team “Myelin plasticity and regeneration”
Team leader
Brahim NAIT OUMESMAR PhD, DR2, INSERM
Violetta ZUJOVIC PhD, CR1, INSERM
Repair
Main domain: Cellular & molecular neurosciences
Subdomain : Clinical & translational neurosciences

Brahim NAIT OUMESMAR & Violetta ZUJOVIC’s team aims at providing better insight into the mechanisms of myelin plasticity and regeneration. Compelling evidences indicate that oligodendrocyte progenitor cells (OPCs) sense neuronal activity and immune cells signaling, highlighting the importance of these crosstalk’s in (re)-myelination. Therefore, our research project will rely on three major aims to decipher:
  • The role of i)neuronal activity and ii) immune cells in oligodendrocyte differentiation, regeneration and myelin repair, unraveling their relevance in human oligodendrocyte differentiation;
  • To develop innovative tools to identify and assess the therapeutic value of new pro-myelinating compounds.
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