Journal
MOLECULAR THERAPY
Volume 18, Issue 4, Pages 754-765Publisher
CELL PRESS
DOI: 10.1038/mt.2009.312
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Funding
- Centro de Investigacion Medica Aplicada, University of Navarra
- EU
- MEC [SAF2005-03131, 2008-03300]
- Fondo de Investigacion sanitaria [PI061475, PI060932, PI0902639]
- Departamento de Educacion del Gobierno de Navarra, Departamento de Salud del Gobierno de Navarra (Beca Ortiz de Landazuri)
- Redes tematicas de investigacion cooperativa RETIC [RD06/0020/0065]
- Red IMMUNONET-SUDOE
- RTICC
- Fundacion Mutua Madrilena
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Repeated administration of gene therapies is hampered by host immunity toward vectors and transgenes. Attempts to circumvent antivector immunity include pharmacological immunosuppression or alternating different vectors and vector serotypes with the same transgene. Our studies show that B-cell depletion with anti-CD20 monoclonal antibody and concomitant T-cell inhibition with clinically available drugs permits repeated liver gene transfer to a limited number of nonhuman primates with recombinant adenovirus. Adenoviral vector-mediated transfer of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene was visualized in vivo with a semiquantitative transgene-specific positron emission tomography (PET) technique, liver immuno-histochemistry, and immunoblot for the reporter transgene in needle biopsies. Neutralizing antibody and T cell-mediated responses toward the viral capsids were sequentially monitored and found to be repressed by the drug combinations tested. Repeated liver transfer of the HSV1-tk reporter gene with the same recombinant adenoviral vector was achieved in macaques undergoing a clinically feasible immunosuppressive treatment that ablated humoral and cellular immune responses. This strategy allows measurable gene retransfer to the liver as late as 15 months following the first adenoviral exposure in a macaque, which has undergone a total of four treatments with the same adenoviral vector.
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