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

被引：121
作者：
An, Dong Sung
Donahue, Robert E.
Karnata, Masakazu
Poon, Betty
Metzger, Mark
Mao, Si-Hua
Bonifacino, Aylin
Krouse, Allen E.
Darlix, Jean-Luc
Baltimore, David
Qin, F. Xiao-Feng
Chen, Irvin S. Y.
机构：
[1] CALTECH, Div Biol, Pasadena, CA 91125 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, AIDS Inst, Dept Hematol & Oncol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, AIDS Inst, Dept Microbiol, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, AIDS Inst, Dept Immunol, Los Angeles, CA 90095 USA
[5] Univ Calif Los Angeles, David Geffen Sch Med, AIDS Inst, Dept Mol & Med Genet, Los Angeles, CA 90095 USA
[6] Ecole Normale Super Lyon, Inst Natl Sante & Rech Med, Unite Virol Humaine 412, LaboRetro, F-69364 Lyon, France
[7] Univ Texas, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA
[8] NHLBI, Hematol Branch, Rockville, MD 20850 USA
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 32期
关键词：
short-hairpin RNA; siRNA; rhesus macaque; gene therapy;
D O I：
10.1073/pnas.0705474104
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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.
引用
收藏
页码：13110 / 13115
页数：6
相关论文
共 36 条
[1]   Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning [J].
Aiuti, A ;
Slavin, S ;
Aker, M ;
Ficara, F ;
Deola, S ;
Mortellaro, A ;
Morecki, S ;
Andolfi, G ;
Tabucchi, A ;
Carlucci, F ;
Marinello, E ;
Cattaneo, F ;
Vai, S ;
Servida, P ;
Miniero, R ;
Roncarolo, MG ;
Bordignon, C .
SCIENCE, 2002, 296 (5577) :2410-2413
[2]   Optimization and functional effects of stable short hairpin RNA expression in primary human lymphocytes via lentiviral vectors [J].
An, Dong Sung ;
Qin, F. Xiao-Feng ;
Auyeung, Vincent C. ;
Mao, Si Hua ;
Kung, Sam K. P. ;
Baltimore, David ;
Chen, Irvin S. Y. .
MOLECULAR THERAPY, 2006, 14 (04) :494-504
[3]   Lentivirus vector-mediated hematopoietic stem cell gene transfer of common gamma-chain cytokine receptor in rhesus macaques [J].
An, DS ;
Kung, SKP ;
Bonifacino, A ;
Wersto, RP ;
Metzger, ME ;
Agricola, BA ;
Mao, SH ;
Chen, ISY ;
Donahue, RE .
JOURNAL OF VIROLOGY, 2001, 75 (08) :3547-3555
[4]   Safety and efficacy of a lentiviral vector containing three anti-HIV genes - CCR5 ribozyme, tat-rev siRNA, and TAR decoy - in SCID-hu mouse-derived T cells [J].
Anderson, Joseph ;
Li, Ming-Jie ;
Palmer, Brent ;
Remling, Leila ;
Li, Shirley ;
Yam, Priscilla ;
Yee, Jiing-Kuan ;
Rossi, John ;
Zaia, John ;
Akkina, Ramesh .
MOLECULAR THERAPY, 2007, 15 (06) :1182-1188
[5]   GENE-THERAPY - INTRACELLULAR IMMUNIZATION [J].
BALTIMORE, D .
NATURE, 1988, 335 (6189) :395-396
[6]   The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes [J].
Bleul, CC ;
Wu, LJ ;
Hoxie, JA ;
Springer, TA ;
Mackay, CR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (05) :1925-1930
[7]   Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease [J].
Cavazzana-Calvo, M ;
Hacein-Bey, S ;
Basile, CD ;
Gross, F ;
Yvon, E ;
Nusbaum, P ;
Selz, F ;
Hue, C ;
Certain, S ;
Casanova, JL ;
Bousso, P ;
Le Deist, F ;
Fischer, A .
SCIENCE, 2000, 288 (5466) :669-672
[8]   Human immunodeficiency virus type 1 coreceptors participate in postentry stages in the virus replication cycle and function in simian immunodeficiency virus infection [J].
Chackerian, B ;
Long, EM ;
Luciw, PA ;
Overbaugh, J .
JOURNAL OF VIROLOGY, 1997, 71 (05) :3932-3939
[9]   Real-time quantification of microRNAs by stem-loop RT-PCR [J].
Chen, CF ;
Ridzon, DA ;
Broomer, AJ ;
Zhou, ZH ;
Lee, DH ;
Nguyen, JT ;
Barbisin, M ;
Xu, NL ;
Mahuvakar, VR ;
Andersen, MR ;
Lao, KQ ;
Livak, KJ ;
Guegler, KJ .
NUCLEIC ACIDS RESEARCH, 2005, 33 (20) :e179.1-e179.9
[10]   Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene [J].
Dean, M ;
Carrington, M ;
Winkler, C ;
Huttley, GA ;
Smith, MW ;
Allikmets, R ;
Goedert, JJ ;
Buchbinder, SP ;
Vittinghoff, E ;
Gomperts, E ;
Donfield, S ;
Vlahov, D ;
Kaslow, R ;
Saah, A ;
Rinaldo, C ;
Detels, R ;
OBrien, SJ .
SCIENCE, 1996, 273 (5283) :1856-1862
1234