Ein lentiviraler Vektor für die Transduktion von G0-arretierten Zellen. Analyse genetischer Determinanten

• Antragsteller: Professor Dr. Klaus Cichutek
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 22216884

Lentiviral vectors (LVs) are superior to gammaretroviral vectors derived from murine leukaemia virus (MLV) since they allow transduction of non-mitotic cells. However, they are inefficient in mediating gene transfer into particular quiescent primary human cells such as non-stimulated lymphocytes, monocytes, or CD34+ haematopoietic progenitor cells, probably due to the low activation status and the GO cell cycle state of these cells. In contrast, a lentiviral vector derived from simian immunodeficiency virus (SIV) smmPBj has been shown to mediate transduction of human cell lines arrested in the Go state of the cell cycle (haematopoietic stem cells are believed to be in that cell cycle state) and of human primary cells such as freshly isolated monocytes in GQ. PBj vectors will therefore significantly extend human gene therapy perspectives. Since the parental virus of this vector is a highly pathogenic SIV strain which causes an acute enteropathy in monkeys, SIVsmmPBj vectors offer also the chance of accelerated safety studies compared to vectors derived from other lentiviruses which do not induce an acute disease in these species. Based on the development of a minimal PBj vector which allows efficient gene transfer into human haematopoietic cells which cannot be efficiently transduced by other lentiviral vectors, we aim at (i) identifying genetic viral and cellular determinants of gene transfer into Go cells such as primary monocytes or stem cells, (II) generation of a third-generation PBj vector and (iii) testing PBj vector safety in animals with respect to insertional oncogenesis.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1230: Mechanisms of gene vector entry and persistence
• Beteiligte Person: Professor Dr. Matthias Schweizer