Team 8- Inflammatory Myopathies & Innovative Therapies

O. Benveniste

Team leader : Olivier Benveniste
The team lead by Prof. Olivier Benveniste is committed to perform translational medicine studies focused on muscle immunology (including primary inflammatory myopathies (myositis), and immune responses elicited by enzyme replacement therapy procedures targeting muscle lysosomial diseases).

Myositis projects

Auto-immune myopathies are a rare and heterogeneous acquired muscle diseases since both muscular and extra-muscular manifestations may differ, leading to identify subgroups of patients based on clinical phenotype and muscle pathology. Life-threatening complications still exist. The pathophysiology of these disabling diseases remains largely unknown. To date, most of these auto-immune myopathies are associated with newly described myositis specific auto-antibodies (MSA). Whereas each MSA is associated with a relatively homogenous clinical phenotype, nothing is known concerning the specificity of muscle pathology associated with a given MSA. In addition, the specificity of muscular immune response associated with a given MSA is not described as well.

Our goal is to revisit the classification, physiopathology and then treatment of the different inflammatory myopathies based on their MSA.

To achieve this goal and since the opening of the team, we have setting-up an e-CRF for myositis. We established the ethical management rules and obtained approval from ethical committee and CCTIRS. We launched this e-CRF in our center but also in 8 other centers in France. We started to perform patient characterization and phenotyping (998 patients are in the database in April 2015, and for 230 of them we already completed clinical/biological notably serological/imaging/pathology parameters). We hired a PhD student with a project in epidemiology to feed and analyse this database. In parallel, we established sample banking in “Myosites ADN-ARNthèque Serothèque Cellulothèque” (MASC study) (reference Codecoh: DC-2011-1445). Using these tools, we sharply characterize inflammatory responses of patients, effects of MSA on myoblasts primary cultures / tubes, or in vivo on mouse.

Lysosomial diseases and immune reactions elicited by enzyme replacement therapies

Pompe disease (PD) is an inherited metabolic myopathy caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Enzyme replacement therapy (ERT) has improved the outcome of PD, however immune responses directed against infused recombinant GAA are not uncommon and in some cases prevent therapeutic efficacy. While it is clear that the development neutralizing antibodies to GAA is associated with a poor prognosis in infantile PD patients, in subjects with the milder form of the disease, the late-onset Pompe diseases (LOPD), immunity against GAA in ERT is poorly characterized both from an immunological and a clinical perspective.
The aim of the current study is to better characterize T cell responses to recombinant GAA in LOPD subjects with high vs. low antibody titers to the protein and to compare results in untreated LOPD subjects and healthy donors.

A similar approach is applied in Fabry disease, another lysosomal disorder eligible for ERT.

Team members

Olivier Benveniste, PU-PH, Team leader, Head of the Department of Internal Medicine et Clinical Immunology, Myositis National Network Coordinator
Yves Allenbach, MCU-PH, Co-team leader
Pascal Laforet, PH, Pompe disease National Network Coordinator
Olivier Lidove, PH, Fabry disease National Network Coordinator
Damien Amelin, Ingeneer
Akinori Uruha, Post-doc
Leandro Ladislau, Post-doc
Gaelle Dzangue-Tchoupou, Pre-doc
Kubéraka Mariampillai, Pre-doc
Wladimir Mauhin, Pre-doc