Description du projet
Vers des procédures de thérapie génique plus sûres
La thérapie génique appliquée aux hémopathies malignes ou aux maladies hématopoïétiques héréditaires fait intervenir la manipulation génétique ex vivo de cellules souches hématopoïétiques ou progénitrices, qui sont réinjectées au patient. Le principe repose sur le fait que ces cellules vont se fixer à la moelle osseuse et reconstituer un système hématopoïétique et immunitaire sain. Le projet IMPROVING-GT, financé par l’UE, entend remédier aux toxicités associées au conditionnement nécessaire de la moelle osseuse et à la mobilisation des progéniteurs hématopoïétiques, qui réduisent le potentiel de reconstitution des cellules. Les chercheurs identifieront des régimes myéloablatifs et mobilisateurs plus légers dans le but ultime de réduire la toxicité et d’améliorer les résultats cliniques des patients.
Objectif
Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) refers to the transfer of nucleic acids into HSPCs, to either add a new copy of a “healthy” gene or to correct a mutated gene. HSPC-GT is successfully used in clinic to treat patients with hematopoietic malignancies and several inherited diseases of the hematopoietic system. Yet, its current use is accompanied by acute conditioning-related toxicities, which impose a burden on patients and limit its application to the most severe conditions. HSPC-GT requires the following steps: HSPCs are mobilized and harvested from the patient, genetically corrected ex-vivo by gene transfer or gene editing and infused back to the patient, after administration of partial or fully myeloablative conditioning to make space in the bone marrow for the modified cells. Administered HSPCs home to the bone marrow, where they engraft and reconstitute a healthy immune system, theoretically throughout life. However, two major shortcomings undermine the full therapeutic potential of HSPC-GT: (i) a decrease in short- and/or long-term engraftment potential due to the ex vivo manipulation of HSPCs and (ii) a toxicity in the hematopoietic and non-hematopoietic organs related to the conditioning regimens, which are based on cytotoxic drugs. The project IMPROVING-GT proposes to develop innovative schemes to increase engraftment and dodge genotoxic conditioning, which are some of the most coveted but still unaccomplished goals of HSPC-GT. The candidate aims to (1) increase the fitness of genetically modified HSPCs by uncovering new players of engraftment and (2) bypass the toxic conditioning requirement by exploiting enhanced mobilization reagents. IMPROVING-GT will pave the way towards non or milder genotoxic regimens, which should greatly minimize undesirable toxicity of current treatments and ameliorate patients’ outcome. Moreover, it may help broadening applications of HSPC-GT to more diseases, including patients with lower disease burden.
Champ scientifique
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Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
20132 Milano
Italie