Journal
BLOOD
Volume 134, Issue 16, Pages 1298-1311Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019000040
Keywords
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Categories
Funding
- National Institutes of Health (NIH), National Heart, Lung, and Blood Institute
- NIH National Institute of General Medical Sciences
- NIH National Institute of Allergy and Infectious Diseases
- Office of Research Infrastructure Programs of the National Institutes of Health, National Cancer Institute
- National Science Foundation
- Fred Hutchinson Cancer Research Center (FHCRC) [CA042056, U54GM103368, P30 AI036214, R01HL116221, U54DK106829, P51RR000167, NSF/DGE-1346837]
- Turner B. and Lesly Starr Shelton Endowment Scholarship
- FHCRC Development
- Jose Carreras/E. Donnall Thomas Endowed Chair for Cancer Research
- Fred Hutch Endowed Chair for Cell and Gene Therapy
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
- NIH National Institute of General Medical Sciences [R01GM84994]
- Research Corporation for Science Advancement
- [P30 CA015704]
- [5T32AI007354]
- [F30 HL137563]
- [HL115128]
- [HL098489]
- [AI096111]
- NATIONAL CANCER INSTITUTE [ZIABC011756] Funding Source: NIH RePORTER
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Therapeutic gene delivery to hematopoietic stem cells (HSCs) holds great potential as a life-saving treatment of monogenic, oncologic, and infectious diseases. However, clinical gene therapy is severely limited by intrinsic HSC resistance to modification with lentiviral vectors (LVs), thus requiring high doses or repeat LV administration to achieve therapeutic gene correction. Here we show that temporary coapplication of the cyclic resveratrol trimer caraphenol A enhances LV gene delivery efficiency to human and nonhuman primate hematopoietic stem and progenitor cells with integrating and nonintegrating LVs. Although significant ex vivo, this effect was most dramatically observed in human lineages derived from HSCs transplanted into immunodeficient mice. We further show that caraphenol A relieves restriction of LV transduction by altering the levels of interferoninduced transmembrane (IFITM) proteins IFITM2 and IFITM3 and their association with late endosomes, thus augmenting LV core endosomal escape. Caraphenol A-mediated IFITM downregulation did not alter the LV integration pattern or bias lineage differentiation. Taken together, these findings compellingly demonstrate that the pharmacologic modification of intrinsic immune restriction factors is a promising and nontoxic approach for improving LV-mediated gene therapy.
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