Neuroimmunology and peptide therapy (Équipe S. Muller)
Our group concentrates its research activity on the misdirected immune responses occurring in autoimmune diseases, primarily systemic lupus erythematosus (SLE), and on the discovery of new druggable molecules designed to specifically immunoregulate these diseases.
SLE is a multigenic chronic autoimmune disease characterized by the deposition of autoantibodies and immune complexes that can affect every organ system and whose etiology still remains largely unknown. If the use of corticosteroids and immunosuppressant enabled health staff [...]to provide much better patient care in the 1950s, these drugs, which still represent the mainstay of treatment, have unfortunate side effects, counter-indications and definite toxicity that can contribute to disease morbidity. Some years ago, our group discovered a peptide which we called P140 that exhibits impressive protective effects in MRL/lpr mice that develop a strong lupus-like disease. In a multicenter, randomized, placebo-controlled phase-IIb study for lupus, P140/LupuzorTM was found to be safe and met its primary efficacy end points, confirming pre-clinical data generated in MRL/lpr lupus-prone mice. It has been evaluated in phase III-clinical trials in the US, Europe and Mauritius. It is currently in a second phase III study in the US.
P140 peptide was found to bind HSPA8/HSC70 chaperone protein and decrease its expression, which we discovered to be enhanced in lupus conditions. This interaction, demonstrated both in vitro and in vivo, destabilizes the HSPA8 binding to other chaperones, such as HSP90AA1, and consequently affect its biological activity. We also showed that administration of P140 into MRL/lpr mice reduces the autophagic flux in antigen-presenting B cells with an accumulation of macroautophagy markers and a blockade of the excessive chaperone-mediated autophagy process; in mice and patients with lupus, P140 also decreases the abnormally high MHC molecule expression. These effects contribute all to reduce hyperactivation of T and B cell autoreactivity and production, in fine, of pathogenic autoantibodies.
Our on-going studies are particularly focused:
- at the cellular and molecular level, on autophagy processes that appear abnormal in several autoimmune and inflammatory conditions and prove to be a decisive hot point in the pathology of lupus and other acute and chronic inflammatory conditions;
- at the pathophysiological level, in lupus and other models of inflammation, on clinical alteration that progressively emerge, including alterations of microbiome, in relation to autophagy defects, and
- more broadly, on peptide-based strategies developed with the aim of specifically modulating autoreactivity, restoring immune tolerance and reversing the course of diseases in murine models of chronic inflammatory pathologies, including neurological and metabolic diseases.
Now and in the future, we will commit ourselves in the development of strategies designed to administrate therapeutic peptide via a non-invasive way using a variety of nanostructures for their bio-delivery. Efforts will also be devoted to aspects of theranostics with the development of specific chips to identify potential responders to peptide treatment, and of peptide tracking using innovative methods of imaging in living conditions.
The laboratory is located in the Institut de Science et d'Ingénierie Supramoléculaires (ISIS), 8 Allée Gaspard Monge, 67000 Strasbourg
In October 2022, Sylviane delivered 7 lectures in several cities of India, between New Delhi and Bangalore, under the cover of IFCPAR (Indo-French Center for the Promotion of Advanced Research), photos opposite.
Funding sources :
