Exosomes from stem cells for the treatment of radiological burns – EXOCET

Acute high dose irradiation accidents occur every year worldwide, either resulting from the loss of radioactive sources or from over-irradiation following radiotherapies or interventional radiology procedures. In addition, the risk of a terrorist attack has also been seriously considered for recent years. The work undertaken by the partners (IRSN, CTSA) over the last years led to the proposal of a new therapeutic approach for the management of victims of accidental irradiation. This procedure consists in repeated local injections of autologous mesenchymal stromal cells (MSC), associated to a surgical exeresis of the necrotic zones and skin graft or vascularized skin flap. Preclinical studies using animal models showed that MSCs, essentially owing to their strong secretory activity, contribute to control inflammation and promote tissue regeneration by accelerating angiogenesis and reepithelization processes. However, application of this procedure is facing several risks and limits inherent to the use of adult stem cells, such as the limited capacity for large-scale production of clinical grade MSCs, the risk of no validation or loss of functionality of the graft.

The EXOCET project aims to propose an innovative therapeutic product based on the use of extracellular vesicles (exosomes) pour the treatment of radiological burns consecutive to accidental exposure to ionizing radiations.

This project relies on the expertise of the partners in such fields as the clinical management of radiological burns, stem cells and cell therapy. Exosomes will be purified from conditioned, clinical grade culture supernatants of human stem cells: MSCs from bone marrow and MSCs from adipose tissue. Vesicles will be isolated by ultrafiltration and liquid chromatography, and will be characterized by using nanoparticles analyzers. Culture conditions will be modulated in order to optimize the yield and quality of produced exosomes.

Exosomes will be functionally validated through the means of in vitro and ex vivo tests already set up by the partners, aimed at evaluating their pro-angiogenic, immunosuppressive, and reepithelization potential. Therapeutic efficacy of exosomes will be analyzed by using a mouse model of musculo-cutaneous radio-induced lesion after localized hind limb irradiation, set up in the lab. Macroscopic analysis of the lesion (clinical scoring) will be performed on a regular basis after administration of various doses of exosomes, in order to monitor its evolution. Histological, immunohistochemical and molecular analyses of tissue samples at different time points will allow the evaluation of the effect of exosomes on angiogenesis, reepithelization and modulation of inflammation. Blood samples will be obtained in order to monitor different circulating markers of angiogenesis and identify new biomarkers for therapeutic efficacy.

The success of this project may open new perspectives for the clinical transfer of the use of exosomes for the treatment of radiological burns, owing to the set up of the procedures for the production of clinical grade exosomes. In the end, this may lead the partners to apply for an extension of the current AMM MTI-PP received by CTSA for the production of bone marrow-derived MSCs for the treatment of the cutaneous irradiation syndrome. In addition, the biophysical properties of exosomes offer the perspectives transport and storage compatible with use on site or in emergency situation involving mass casualties.