Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates.
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.
An
Dong Sung
DS
Department of Hematology and Oncology, AIDS Institute, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Donahue
Robert E
RE
Kamata
Masakazu
M
Poon
Betty
B
Metzger
Mark
M
Mao
Si-Hua
SH
Bonifacino
Aylin
A
Krouse
Allen E
AE
Darlix
Jean-Luc
JL
Baltimore
David
D
Qin
F Xiao-Feng
FX
Chen
Irvin S Y
IS
D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy; D000818:Animals; D065100:CCR5 Receptor Antagonists; D015316:Genetic Therapy; D015497:HIV-1; D018380:Hematopoietic Stem Cell Transplantation; D008214:Lymphocytes / Q000821:virology; D008253:Macaca mulatta; D034622:RNA Interference; D019713:Receptors, CCR5 / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000254:growth & development
D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5