Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates
Published online before print August 1, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0705474104
Dong Sung An *, Robert E. Donahue {dagger}, Masakazu Kamata {ddagger}, Betty Poon {ddagger}, Mark Metzger {dagger}, Si-Hua Mao {ddagger}, Aylin Bonifacino {dagger}, Allen E. Krouse {dagger}, Jean-Luc Darlix {sect}, David Baltimore ¶||, F. Xiao-Feng Qin **, and Irvin S. Y. Chen {ddagger}||
Departments of *Hematology and Oncology and {ddagger}Microbiology, Immunology, and Molecular Genetics and Medicine, AIDS Institute, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095; {dagger}Hematology Branch, National Heart, Lung, and Blood Institute, 5 Research Court, Rockville, MD 20850; ¶Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125; {sect}LaboRetro, Unité de Virologie Humaine, Institut National de la Santé et de la Recherche Médicale, no. 412, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364 Lyon, France; and **Department of Immunology, M. D. Anderson Cancer Center, University of Texas, Unit 901, 7455 Fannin Street, Houston, TX 77030
Contributed by David Baltimore, June 13, 2007 (sent for review March 4, 2007)
RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.
Author contributions: D.S.A., R.E.D., M.K., B.P., D.B., F.X.-F.Q., and I.S.Y.C. designed research; D.S.A., R.E.D., M.K., B.P., M.M., S.-H.M., A.B., and A.E.K. performed research; J.-L.D. contributed new reagents/analytic tools; D.S.A., R.E.D., M.K., B.P., and I.S.Y.C. analyzed data; and D.S.A., R.E.D., and I.S.Y.C. wrote the paper.
The authors declare no conflict of interest.
||To whom correspondence may be addressed.
David Baltimore, E-mail: baltimo@caltech.edu
Irvin S. Y. Chen, E-mail: syuchen@mednet.ucla.edu
www.pnas.org/cgi/doi/10.1073/pnas.0705474104 |
