IMPROVING-GT · Innovative strategies to increase engraftment of engineered hematopoietic stem cells and bypass genotoxic conditioning, toward the next-generation gene therapy

Innovative strategies to increase engraftment of engineered hematopoietic stem cells and bypass genotoxic conditioning, toward the next-generation gene therapy

The IMPROVING-GT project was centered around the advancement of hematopoietic stem/progenitor cell gene therapy (HSPC-GT), a promising therapeutic approach for treating various genetic diseases. The administration of HSPC-GT involves the ex vivo genetic correction of HSPCs, which are then infused back into the patient after a myeloablative conditioning process to deplete the bone marrow and make space for the modified cells​​. The issue being addressed by the project is two-fold: the challenges associated with the engraftment of these genetically corrected HSPCs, and the toxicities related to the conditioning regimes required for successful transplantation. These are significant obstacles in the field of gene therapy as they can limit the effectiveness of the treatment and pose substantial risks to patients. Addressing these challenges is crucial for society as it has the potential to transform the treatment landscape for patients suffering from genetic diseases by improving the safety and efficacy of gene therapies. The ultimate goal is to fully leverage the life-saving capabilities of HSPC-GT by minimizing its associated risks and increasing its clinical success rate. The overall objectives of the IMPROVING-GT project were: * To maximize the engraftment of HSPCs and counteract the negative impacts of ex-vivo manipulation. This was pursued by enhancing human HSC engraftment through the transient overexpression of selected targets involved in various biological processes such as phagocytosis protection, homing, migration, retention, and self-renewal. * To develop and optimize non-genotoxic conditioning protocols by exploiting enhanced mobilization reagents. This objective aimed to eliminate the need for harmful conditioning by using advanced mobilization agents that could lead to substantial, albeit temporary, emptying of bone marrow niches, thus creating a window for the engraftment of genetically modified cells. The project successfully demonstrated a proof-of-principle for a novel, low-burden, genotoxic-free HSPCs transplant protocol that could potentially replace the current high-risk conditioning regimens with a safer alternative. This represents a substantial step toward reducing the toxicity associated with current HSPC-GT protocols, ultimately improving patient outcomes and expanding the applicability of gene therapies​​.

Data: CORDIS, © European Union