Exploiting microRNA-regulation to improve the reach and safety of hematopoietic stem cell manipulation

• Antragsteller: Dr. Bernhard Gentner
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 30450217

The clinical application of gene therapy is hampered by inefficient delivery and long-term expression of the transgene in the target cell population. Retroviral vectors as gene delivery platforms allow stable transgene expression over extended time periods. To be efficient, the retroviral vector system depends on the transduction of stem cell populations that self-renew and continuously give rise to a huge number of differentiated progeny in vivo. Expressing foreign genes in stem cells in an unregulated fashion carries the risk of inducing cancer. The first key objective of the intended research is to restrict transgene expression to a subset of hematopoietic progenitor cells that are less susceptible to cancer formation than primitive stem cells but on the other hand serve the purpose of delivering the therapeutic gene in ample quantity. The pool of gene-expressing cells will be replenished by stem cells that contain the transgene in a silenced form which becomes activated upon differentiation. This objective will be achieved by exploiting a posttranscriptional, endogenous regulatory network consisting of microRNAs. The second key objective is to exploit the increased safety of such a differentiation stage-dependent expression strategy to express growth-regulatory genes that allow safe enrichment of gene-modified cells and thus enhance efficacy and applicability of gene therapy for a wider range of diseases.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: Italien
• Gastgeber: Professor Dr. Luigi Naldini