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Published August 7, 2007 | Published + Supplemental Material
Journal Article Open

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

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.

Additional Information

© 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.

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Published - ANDpnas07.pdf

Supplemental Material - ANDpnas07fig5.pdf

Supplemental Material - ANDpnas07fig6.pdf

Supplemental Material - ANDpnas07fig7.pdf

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Additional details

Created:
August 22, 2023
Modified:
October 16, 2023