Avoiding MDS/AML in genetic therapy for FA with complex retroviral vectors

• Antragsteller: Professor Dr. Helmut Hanenberg
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 22771517

Fanconi Anemia (FA) is recessive DNA double strand repair disorder where due to the accumulation of DNA damage over time, a high propensity exists to develop malignancies. Spontaneously occurring natural reversions of inherited mutations in stem cells of FA patients that completely correct the FA-specific defect in the hematopoietic system by repopulation with corrected progeny suggest that FA would be an ideal model disorder for stem cell gene therapy approaches. Therefore, FA stem cell gene therapy is currently implemented in a clinical phase I study with an oncoretroviral vector in a classical four day transduction protocol. Very recently however, Li et al. demonstrated that in vitro manipulation of murine FA stem cells for 2 to 4 days led to the development of MDS and AML in these FA mice independent of any insertional mutagenesis. Here, we propose to develop strategies to avoid any prolonged in vitro manipulation periods by systematically testing vectors derived from complex retroviruses such as foamy viruses (FV) or lentivirus (LV) for genetic correction of FA mice. These vector systems have been described by us and others to be highly efficient for gene delivery into hematopoietic stem cells in short overnight transduction protocols and therefore appear to be ideally suited for genetic therapy in FA.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1230: Mechanisms of gene vector entry and persistence