ENRICHment of genetically modified hematopoietic stem cells to achieve therapeutic efficacy

• Applicant: Dr. Claudio Mussolino
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568914967

Gene therapy holds great promise for treating hematopoietic disorders, yet its broad application remains limited by several key challenges: low gene modification efficiency, insufficient engraftment of modified cells, and the toxic side effects of chemotherapy, which is required to reduce competition from endogenous, unmodified cells. These limitations hinder the safe and effective use of gene therapy for conditions such as β-hemoglobinopathies, including sickle cell disease, which are among the most common genetic disorders worldwide. This project aims to overcome these barriers by leveraging advanced gene editing technologies to enhance the enrichment and engraftment of genetically modified cells. Specifically, we propose a dual strategy: correcting the underlying genetic defect while inactivating dispensable cell surface markers. This selective inactivation will enable efficient selection of modified cells that lack these markers, facilitating engraftment without the need for a toxic, full-conditioning chemotherapy regimen. This approach not only minimizes patient risk but also improves the therapeutic outcome by significantly increasing the proportion of corrected cells. By applying this innovative strategy to β-hemoglobinopathies and potentially other hematological disorders amenable to gene therapy, this project aims to develop a safer, more effective treatment protocol. The long-term goal is to translate these advancements into clinical practice, offering new therapeutic options for patients suffering from these severe genetic diseases.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professorin Dr. Annarita Miccio, Ph.D.