Inhibition of monocyte production using siRNA against CD115 and M-CSF in autoimmune myocarditis

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Monocytes and macrophages are centrally involved in the progression of various diseases. The applicant was recently able to show that nanoparticle encapsulated siRNA against CCR2 prevents the accumulation of monocytes at the site of lesion. In so far unpublished experiments it was found that this newly developed nanoparticle also localizes to monocyte-producing myeloid progenitor cells. These myeloid progenitor cells, as well as monocytes express Colony Stimulating Factor 1 Receptor (CD115), which binds M-CSF, a cytokine essential for the production, proliferation and differentiation of monocytes.Aim of the here proposed project is to selectively reduce the production of monocytes by silencing CD115 in myeloid progenitors cells and monocytes with nanoparticle encapsulated siRNA. Secondly, with monocytes being main producers of M-CSF themselves, an additional siRNA will be explored to block the synthesis of the cytokine. Following ex vivo- and in vivo- validation experiments it will be tested in the mouse model of autoimmune myocarditis if reduced monocyte production through siRNA-nanoparticles results in a reduction of cardiac inflammation and impacts the outcome of disease.This new approach could facilitate the exclusive modulation of the myeloid cell lineage and offer new therapeutic options in immune therapy.