Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 32, Pages 13110-13115Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705474104
Keywords
short-hairpin RNA; siRNA; rhesus macaque; gene therapy
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Funding
- Intramural NIH HHS Funding Source: Medline
- NHLBI NIH HHS [1R01HL086409-01, R01 HL086409] Funding Source: Medline
- NIAID NIH HHS [AI39975-05, AI28697, P30 AI028697, R01 AI039975] Funding Source: Medline
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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.
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