An, Dong Sung and Donahue, Robert E. and Kamata, Masakazu and Poon, Betty and Metzger, Mark and Mao, Si-Hua and Bonifadno, Aylin and Krouse, Allen E. and Darlix, Jean-Luc and Baltimore, David and Qin, F. Xiao-Feng and Chen, Irvin S. Y. (2007) Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates. Proceedings of the National Academy of Sciences of the United States of America, 104 (32). pp. 13110-13115. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:ANDpnas07
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PDF (Fig. 5. Lymphocyte cell surface marker expression in EGFP+ or EGFP- lymphocyte population.)
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Abstract
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.
| Item Type: | Article |
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| Additional Information: | Copyright © 2007 by the National Academy of Sciences. Contributed by David Baltimore, June 13, 2007 (received for review March 4, 2007). Published online on August 1, 2007, 10.1073/pnas.0705474104. We thank Drs. Kathie Grovit Ferbas (University of California, Los Angeles), François-Loïc Cosset (Institut National de la Santé et de la Recherche Médicale, ENSINSERM, France), and Didier Nègre (ENSINSERM, France) for providing reagents and the animal management staff of 5 Research Court (National Heart, Lung and Blood Institute) for assistance. This research was supported by the National Institutes of Health (Grants AI39975-05 and AI28697 to I.S.Y.C. and 1R01HL086409-01 to D.S.A.) and in part by the Intramural Research Program of the National Institutes of Health. 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. This article contains supporting information online at www.pnas.org/cgi/content/full/0705474104/DC1. |
| Subject Keywords: | short-hairpin RNA; siRNA; rhesus macaque; gene therapy |
| Record Number: | CaltechAUTHORS:ANDpnas07 |
| Persistent URL: | http://resolver.caltech.edu/CaltechAUTHORS:ANDpnas07 |
| Alternative URL: | http://dx.doi.org/10.1073/pnas.0705474104 |
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. |
| ID Code: | 9854 |
| Collection: | CaltechAUTHORS |
| Deposited By: | Archive Administrator |
| Deposited On: | 24 Mar 2008 |
| Last Modified: | 26 Dec 2012 09:53 |
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