suppRESsion of immunopathology by nanOparticle deLiVEry of mRNA to monocytes (RESOLVE)

Enhanced immune reactivity against self-antigens is the underlying cause when transplants attack the host (graft vs host disease) or when the host's immune system attack host cells (autoimmune disease). New strategies for treating such serious conditions are needed. This project is developing a nanosystem for targeting and delivering a messenger RNA that can effectively modulate immune tolerance.

The project is expected to affect the research field by providing improved understanding of CFLAR’s target genes in monocytes. As a result of this project, we have also established collaborations with clinicians working on autoimmune disease. We will continue to pursue new academic collaborations based on the project methods.

New treatments to fight immunopathologies originating from enhanced immune reactivity against host self-antigens in the course of transplantation (graft vs host disease, GvHD) and autoimmunity (multiple sclerosis, MS) are urgently needed. Therapeutic approaches based on either systemic or local immunosuppression, which eliminate or suppress polyclonal, autoreactive T-cell specificities, do compromise the entire systemic immunity with many side effects, sometimes even life threatening. The most promising strategies are represented by either restoration or de novo induction of cells able to induce tolerance. Among these cells, key to this project, are the immune regulatory cells of myeloid origin defined as monocytic myeloid-derived suppressor cells (MO- MDSCs). The tolerogenic ability of these cells can be increased by acting on a pathway involved in regulating their apoptosis by the administration of genetic material, such as specific mRNA. The members of the present Consortium have identified a main pathway and some of the possible molecular targets that will be further studied and validated within the following years. Thanks to the present project, we will be able to develop, design and produce efficient new nanosystems (lipid nanocapsules- TRL4, lipid nanoparticles-TRL4 and polymeric biodegradable nanoparticles- TRL3) able to specifically target MO-MDSCs in vivo and effectively deliver mRNA. The nanosystems will be also GMP produced by the development of new microfluidic approaches. We will demonstrate the specific expression of the protein(s) involved in the identified tolerogenic pathways, both at the cellular and tissue level, assess the in vivo nanosystem biodistibution, and their therapeutic efficacy in mouse models of GvHD and MS. We have organized a competitive Consortium involving a multidisciplinary work plan, which will benefit from the academic, industrial and clinical expertise of the participants to guarantee the success of the RESOLVE project.