STEP’s primary objective is to collect all necessary preclinical data on the efficacy and safety of synchrotron-generated microbeams to make possible a First-in-man clinical trial in patients with refractory mesio-temporal lobe epilepsy in the aftermath. STEP represents the transition between 20 years of basic research on Microbeam Radiation Therapy (MRT) and the clinical development of an innovative radiosurgery approach of brain diseases. During the last twenty years, the extremely high flux of photons generated by 3rd generation synchrotrons, has enabled the development of novel irradiation strategies holding great promises for innovative radiotherapy. In particular, the possibility to split weakly diverging synchrotron-generated X-rays into arrays of 50-µm wide microbeams, separated by 200-800 µm, has allowed the emergence of the MRT. Several pre-clinical studies performed by STEP partners and other groups have shown that MRT offers a particularly safe procedure to transect or lesion specific brain regions without the usual tissular, vascular or behavioral side effects of conventional radiotherapy. The collaboration between engineers, researchers and clinicians of the Biomedical Beamline (ID17) at the European Synchrotron Radiation Facility (ESRF), INSERM, and University Hospital of Grenoble-Alpes has shown the efficacy of MRT in animal models of Epilepsy to suppress seizures and neuronal synchronization over several months, without histological or functional deleterious side effects. Therefore, MRT has the potential to become a disruptive technology for treating diseases where the target is closely surrounded by tissues whose function should be preserved, as in focal epilepsies and several other neurological diseases. Our preclinical expertise and the recent experience of patient irradiation at the ESRF, as well as the close collaboration with the Grenoble University Hospital should make the First-in-man clinical trial of MRT possible in 2025. To reach this ambitious goal, STEP will determinate the optimal MRT procedures for an efficient seizure suppression in a rat model of mesiotemporal lobe epilepsy (WP1) and will correlate this information with toxicity thresholds determined in normal rats and minipigs (WP2). These data will help to prepare the documentation required by regulatory and safety French agencies and to design an adapted protocol for the first safety clinical trial in epileptic patients (WP3). The choice to first consider mesiotemporal lobe epilepsy (MTLE) is motivated by several aspects: (i) it is a typical and well described drug-resistant focal epilepsy; (ii) surgical resection of the epileptic zone following craniotomy, is the current gold-standard therapeutic option for this form of epilepsy, is effective in 50 to 80% of cases, but remains risky and has a significant cost for the Health Systems; (iii) the Grenoble University Hospital epilepsy surgery program has accumulated a strong expertise of MTLE patients so that obtaining a significant cohort for the clinical trials should be straightforward; (iv) animal models of MTLE have been well described and members of the consortium already have the expertise to use such models. All members of the consortium have the complementary expertise to conduct this project and have been working together for more than 5 years. The strengths of STEP relies on high-level and robust preclinical studies, which pave the way for a smooth translation towards Phase I clinical trials. We believe that STEP will provide a disruptive therapeutic approach, potentially applicable outside the epilepsy field.