Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates
- 7 August 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 104 (32) , 13110-13115
- https://doi.org/10.1073/pnas.0705474104
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.Keywords
This publication has 39 references indexed in Scilit:
- 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 CellsMolecular Therapy, 2007
- Chemokine Antagonists as Therapeutics: Focus on HIV-1Annual Review of Medicine, 2007
- Optimization and Functional Effects of Stable Short Hairpin RNA Expression in Primary Human Lymphocytes via Lentiviral VectorsMolecular Therapy, 2006
- Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathwaysNature, 2006
- Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarityRNA, 2006
- Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative ConditioningScience, 2002
- High Levels of Transduction of Human Dendritic Cells with Optimized SIV VectorsMolecular Therapy, 2002
- Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 DiseaseScience, 2000
- Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural GeneScience, 1996
- Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor geneNature, 1996