Our goal is to apply for to the MSCA Doctoral Networks in 2023 to train highly skilled doctoral candidates, stimulate their creativity, enhance their innovation capacities, and boost their employability in the emerging field of Epigenetics and Epitranscriptomics. Our consortium called “Chemical analysis and manipulation of epitranscriptomic and epigenetic patterns” (CAME-EPICS) gathers 8 academic partners (6 beneficiaries and 2 partners) and 6 non-academic partners (6 beneficiaries) with complementarity knowledge/expertise, whose role and expertise are crucial for the application-driven research and training activities towards solving societal challenges, entrepreneurship and health care issues. The partners from the non-academic sector will actively participate in all aspects of the training program. The expertise brought by the different partners covers nucleosides and nucleic acids chemistry, analytical chemistry, biochemistry and cellular biology, which will ensure the high quality of an interdisciplinary training of the PhD students in the field of nucleic acids chemistry. Noteworthy, in academia or in industry, there is a growing and urgent need of scientists able to bridge nucleic acids chemistry and biology to fully explore epigenetic and epitranscriptomic processes. Indeed, the recent success of mRNA vaccines has clearly pushed many companies to re-investigate the broad field of nucleic acid chemical modifications in two directions: the use of modified nucleic acids for treatments and vaccins or the search for new drugs (small molecule entities or synthetic biomolecules) that can alter the epigenetic or epitranscriptomic signature of a pathology. In both cases, chemists trained in this interdisciplinary field are very rare and the current supply on the employment market does not satisfy the considerable demand for this type of profile. Our consortium will fill the gap in this field, within the MSCA DN, and will bring the chemical skills and experience necessary to explore and understand at the molecular level the epigenetic and epitranscriptomic fields.

The main objective of DIAMESTAR project is to evaluate the efficacy of a new small interfering RNA(siRNA)/nanocarrier complex to treat Ewing sarcoma (ES) metastatic tumor xenografted on mice, when this nanomedicine is directed by a fragment of antigen-binding (Fab) against a membrane protein overexpressed in ES cells. Ewing sarcoma is a rare, mostly pediatric bone cancer, with a bad prognosis when metastatic. It is an orphan disease with very few therapeutic options. The oncogene we shall target is a fusion oncogene EWS-FLI1 considered as the main cause of Ewing sarcoma. EWS-FLI1 is a paradigm of fusion oncogenes over the 300 discovered in human up to now. siRNA inhibit with a high specificity the expression of any human gene, and can play a key role in treating many diseases (cancers, cardiovascular and neurological diseases). However they are quickly degraded in organism and penetrate poorly in cells. One solution is to use nanocarriers to deliver active siRNA in the cytoplasm where their antisense effect takes place. Various polymeric nanocarriers have been used, but very few have reached clinical trials. We propose an alternative carrier made of a diamond nanocrystal core with a surface chemically modified to bind siRNA electrostatically and bear the Fab intended for targeting. Nanodiamonds present several interests: (i) they are chemically inert and non toxic on cell cultures; (ii) they can be made intrinsically fluorescent or radioactive, hence traceable on long term scale, by embedding color center or tritium, respectively; (iii) their surface can be modified by a variety of methods to provide cationic or anionic charges or to covalently bind biomolecules. The first task will be to synthesize ND/siRNA/Fab complexes of different types (size, traceable properties, surface functions). Then, the toxicity, pharmacokinetics, and biodistribution will be determined in ES tumor xenografted in mice (including a metastatic model) taking advantage of the intrinsic traceability. The localization of the complex within metastases responsible for the low survival rate will be examined carefully. Finally, the therapeutic efficacy will include in vitro and in vivo measurement of EWS-FLI1 inhibition and of the regression of primary and metastatic tumors. The project should give rise to therapeutic solutions ready to enter regulatory preclinical developments.