17 déc.

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Functional genomics and biomarkers of MS treatment

Our team focus on biomarkers associated with response and serious adverse event (SAE) risk in the context of Multiple sclerosis biologic treatment revolution, based on a unique cohort of 1500 patients followed prospectively up to 10 years.

Our main objective is to find biomarkers associated with response and serious adverse events (SAE) prediction during a biological MS treatment. Using Natalizumab (NTZ) as a paradigm, we built up a unique prospective multicentric cohort of 1500 European MS patients (The Best-MS FP7 project) that we followed for up to 10 years using clinical and radiological information as well as biological samples.

We proposed that L-selectin (CD62L) expression in peripheral blood mononuclear cells (PBMC) could be considered as a new risk minimization factor for progressive multifocal leukoencephalopathy (PML) since a 9-fold lower percentage of CD62L was correlated with the risk of PML. It was later confirmed that low CD62L increased the relative risk of PML by 55. Low CD62L values were also associated with AIDS-related PML. The determination of CD62L levels at 2 years of treatment with NTZ was a reliable marker of risk of PML, diagnosed up to 35 infusions later (sensitivity 80%, specificity 87%, hazard ratio=7). We are now performing a prospective study (BEST-MS) in high-risk patients (JCV index >= 0.9 and more than 18 months NTZ) in order to replicate the results found in the retrospectively analyzed BIONAT cohort and to determine optimal thresholds.

We investigate the therapeutic use of CCR5 antagonists in PML-associated immune reconstitution inflammatory syndrome and found that it is supported by strong expression of CCR5 on CD8+ T cells. Our second objective is to investigate the immunogenetics of MS. We found a positive association for TYK2. We showed that TYK2 protective polymorphisms is linked to a Th2 pathway upregulation. We are currently using an omic approach with a GWAS, exome sequencing, RNA sequencing, miRNA, methylome, and microbiote biomarkers in order to propose the best benefit to risk ratio.

Selected publications

Lebrun C, Cohen M, Pignolet B, Seitz-Polski B, Bucciarelli F, Benzaken S, Kantarci O, Siva A, Okuda D, Pelletier D, Brassat D; on behalf SFSEP, BIONAT Network; RISC.
Interleukin 17 alone is not a discriminant biomarker in early demyelinating spectrum disorders.
J Neurol Sci. 2016 Sep 15.

Pignolet B, Schwab N, Schneider-Hohendorf T, Bucciarelli f, Outteryck O, ongagna JC, De seze J, Brochet B, Ouallet jc, Debouverie M, Pittion S, Defer G, Derache N, Hautecoeur P, Tourbah A, labauge P, Castelnovo G, Clavelou P, berger E, Pelletier J, Rico A, Zephir H, Laplaud D, Wiertlewski S, Camu w, Thouvenot e, casez O, moreau T, fromont A, Vukusic S, papeix c, Biotti D, Averseng-peaureaux D, Vermersch P, Comabella M, Lebrun-frenay C, Wiendl H, Brassat D.
CD62L test at 2 years of Natalizumab predicts progressive multifocal leukoencephalopathy
Neurology 2016 (in press)

Last updated November 9, 2016

Centre de physiopathologie de Toulouse Purpan - CHU Purpan - BP 3028 31024 Toulouse Cedex 3
Inserm University of Toulouse Université Toulouse III - Paul Sabatier