"Gentherapie hämatopoietischer Stammzellen für vererbte Erkrankungen"

Stable retrovirus mediated gene transfer into human hematopoietic CD34+ cells with repopulating capacity has a significant potential for the treatment of a variety of hereditary and acquired diseases and as an adjuvant in the treatment of tomours. The promise of clinical gene transfer has recently been highlighted by treatment of SCID-X1 disease, in which the transgene confers a strong selective advantage to transduce lymphoid progenitors, and in an initial study directed at transfer of the multidrug resistance 1 gene, where a selective pressure can be exercised in vivo. These successes were reached with conventional retrovirus vectors. The moderate transduction efficiency of the transplanted CD34+cell is amenable to further improvement which will be required to treat many other clinical conditions that can potentially be cured by gene therapy. Despite these recent achievements, retrovirus/lentivirus mediated gene transfer and its clinical application is still limited by low transduction frequencies in long term repopulating stem cells of primates and man. Objectives are therefore: * To validate gene therapy for example diseases and set the standard for quality, safety and efficacy of retro-/lentivirus mediated gene therapy in hematopoietic stem cells; selected diseases are severe combined immune deficiencies, i.e., X-linked SCID and Rag-1 or Rag-2 deficiency, mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), Blackfan-Diamond anemia and Gaucher's disease. These disease entities have been selected on the basis of existing specific animal models and are together representative for most candidate diseases eligible for gene therapy. * To construct state-of-the art retroviral/lentiviral vectors. * To establish the long-term sustained engraftment of the transduced stem cells and polyclonal expression of the exogenous genes, as well as safety, minimal toxicity and efficacy in preclinical animal models. * To provide reagents and proof of safety and efficacy to enable clinical applications and to evaluate the outcome of an initial clinical trial, especially with regard to the biology and clonal activity of the engrafted transduced cells.

Weitere Informationen: http://www.mol-med.uni-freiburg.de
Ansprechpartner: Annette Deichmann
Tel: 0761/203-9612
Email: christof.kalle@uniklinik-freiburg.de

Projektbeginn: 2002
Projektende: 2004

Prof. Dr. Christoph von Kalle, Prof. Dr. Christoph Peters
Stellvertretung: Dr. Manfred Schmidt
Albert-Ludwigs-Universität Freiburg
Institut für Molekulare Medizin und Zellforschung (IMMZ)
Zentrum für Biochemie und Molekulare Zellforschung (ZBMZ)
Stefan-Meier-Str. 17
79104 Freiburg i. Br.

Telefon: +49-761-203-9600/9601
Fax: +49-761-203-9602
Email: christoph.peters@mol-med.uni-freiburg.de
http://www.mol-med.uni-freiburg.de

G. Wagemaker, Rotterdam, A. Fischer, Paris; S. Karlsson, Lund, Schweden; J. Barquinero, Barcelona; C. Baum, Hannover; O. Danos, Evry, Frankreich

• EU, Framework 5, EU

MPS VI, retrovirus gene therapy, lentivirus gene therapy

• Ailles L, Schmidt M, Santoni de Sio FR, Glimm H, Cavalieri S, Bruno S, Piacibello W, Von Kalle C, Naldini L: Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells. Mol Ther, 2002; 6 (5): 615-26..