An immuno-modulatory phosphorus-based dendrimer for the treatment of Multiple Sclerosis – DENDRI'MS

Multiple Sclerosis (MS) is a Chronic Inflammatory Disease (CID) of autoimmune origin. It is the commonest neurodegenerative disease within the young adult population. Indeed, MS affects 2 million persons worldwide, essentially women. Although efficient treatment have been introduced at the beginning of the 90’s which improve the quality of life of patients, most patients are not getting better, they are just deteriorating at a less rapid rate. The most of these recent therapeutic protocols are based on monoclonal antibodies targeting inflammatory cytokines and their receptors. Unfortunately, they are expensive (around 20,000 $ / patient / year) and present multiple contra-indications. In this context, there is an unmet need for innovating molecules targeting the different aspect of MS (chronic inflammation and neurodegeneration). Our current project aims at answering this expectation.
It is based on our previous findings that synthetic molecules, namely phosphorus-based dendrimers, have anti-inflammatory and immuno-modulatory properties. Dendrimers (“tree-like molecules”) are non linear polymers whose size and structure are perfectly defined. Their diameter is in the nanometric range and therefore they pertain to the “nanoworld”.
In particular, we have shown that a phosphorus-based dendrimer capped with Aza-BisPhosphonate groups (the so-called dendrimer ABP) dramatically inhibits inflammation and bone resorption in a mouse model of experimental arthritis. In this model, dendrimer ABP is given weekly per os or intravenously at a dose of 10 mg per kg. Herein, we propose to evaluate the therapeutic potential of dendrimer ABP in animal models of Experimental Autoimmune Encephalomyelitis (EAE, equivalent to MS in animal models). Clinical, immunological and inflammatory status of animals will be followed up along the study of the efficacy of dendrimer ABP in the EAE models.
Insofar as MS is a CID of the Central Nervous System (CNS), it is crucial to know if dendrimer ABP is able to migrate through the Blood-Brain Barrier (BBB). BBB separates circulating peripheral blood and brain tissue. Theoritically, it cannot be crossed by small and big molecules. Recently, it has been proposed that molecules of intermediate size (i.e. a few nanometers) might migrate through the BBB. This should represent an advantage for dendrimer ABP to exert its immuno-modulatory effect directly in the inflamed CNS of MS patients.
Finally, as dendrimers are very innovating nanomolecules but far from the standards of the pharmaceutical industry, we wish to study the effects of these nanomolecules toward the immune system of healthy animals to assess the immunological innocuity of these drug-candidates. We will conduct this study with non-human primates, the model the closest to Human. This assessment is driven on the one hand by the lack of data regarding the general effects of nanoparticles in living organisms, and on the other hand by the lessons from the deleterious first-in-man clinical trial of an immuno-modulatory monoclonal antibody in UK in 2006 (a multi-organ failure in healthy volunteers referred to as “cytokine storm”).
We handle strong scientific arguments to think that phosphorus-based dendrimer ABP is promising in human healthcare. It is the paradigm of a new family of innovating molecules which could revisit the treatment of CID in general, and of MS in particular.