RPIB - Recherches Partenariales et Innovation Biomédicale

Prerequisite for therapeutic management of sequels from AbdomiNo-pelvic radioTHrapy by local injection of MSC combined with a hydrOgel and an HS-mimetic – ANTHOS

Submission summary

Radiotherapy is still an indisputable component of the management of malignant pelvic diseases. It represents an optimal compromise between control of the tumour and damage to healthy tissue surrounding the tumour, i.e. risk/benefit. Irradiation of healthy areas can cause loss of intestinal integrity, leading to early and late gastro-intestinal complications in some patients, which can be very incapacitating. Surgeons now have a therapeutic armamentarium to relieve symptoms, but no curative treatment is available. For several years now, IRSN (the French National Research Institute) and the Percy CTSA (army blood transfusion centre) have been developing a new treatment strategy using cell therapy and Mesenchymal Stromal Cells (MSC) from bone marrow, raising new hopes for the treatment of radiation-induced tissue damage. In terms of the chronic colonic lesions caused by ionising irradiation, IRSN has shown in different experimental models (mouse, rat and mini-pig) and also in patients (over-irradiated patients from Epinal) that repeated injections of intravenous MSC improves ulcer healing. This healing, however, is incomplete and requires large numbers of stem cells to be injected. Furthermore, in the most serious cases when surgical resection of ulcerated areas is attempted as a last resort, the risks of postoperative morbidity are extremely high.

The aim of this project is to develop a new strategy based on the principle of tissue engineering, combining cell therapy, matricial therapy and biomaterials in order to improve the effectiveness of MSC therapy for severe colorectal radiation ulcers.

The MSC will be injected locally by coloscopy in a rat model, locally irradiated to the colorectal region, which develop lesions similar to those seen in patients suffering from colorectal complications following radiotherapy. This method of injection will allow the take up rate of the transplant to be increased in the area requiring repair. In order to improve MSC survival in the damaged tissue, the cells will be protected in a self-reticulating hydrogel containing HydroxyPropylMethylCellulose (HPMC) developed by LIOAD-UMR_S791. Combined with this hydrogel, the secretory capacities of the MSC will be stimulated by RGTA or ReGeneraTing Agents, which are marketed by the OTR3 company, to increase their therapeutic efficacy.
This proposal groups together skills from different disciplines; biomaterials, regenerative molecules and cell therapy using MSC. Several stages are required to conduct this project:
-development of a hydrogel which can be injected by coloscopy, into which the RGTA are incorporated
-verifying the viability of the MSC in this new construction
-demonstrating increased in vitro secretory capacities of MSC in this construction
-demonstrating the therapeutic efficacy of this construction in vivo in a model of severe colorectal ulceration and in a model of colonic anastomosis after irradiation.

The results obtained from this project will allow optimal treatment to be offered to patients which can be directly used by clinicians (EcellFrance national platform for the production of medicinal products and innovative therapy). It may be given to patient suffering from severe radiation-induced ulcers (grade III lesions according to the SOMA-LENT scale) allowing surgery to be avoided or when surgery is recommended (grade IV lesions) to increase the healing of colonic anastomoses in the irradiated territory.

Project coordination

Noëlle MATHIEU (Laboratoire de Radiopathologie et Therapies Experimentales)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LIOAD Laboratoire d'Ingénierie OstéoArticulaire et Dentaire, UMRS 791
CTSA/U972 Département Recherche et Thérapie Cellulaire CTSA/INSERM U972
OTR3 Société "Organe, Tissu, Régénération, Réparation et Remplacement
IRSN Laboratoire de Radiopathologie et Therapies Experimentales

Help of the ANR 545,502 euros
Beginning and duration of the scientific project: February 2014 - 42 Months

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