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Published on: December 18, 2012
Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized
Ursula Hofer1, Jill E Henley, Colin M Exline
1Keck School of Medicine of the University of Southern California, Los Angeles.
Abstract:
Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4(+) T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies.
Insights
Researchers are developing gene therapies to block CCR5, a key receptor for HIV-1. Modified stem cells in humanized mice show promise for creating HIV-resistant cells, aiding pre-clinical anti-HIV therapy development.
Area of Science:
- Gene therapy
- Immunology
- Virology
Background:
- CCR5 is the primary co-receptor for HIV-1 entry into host cells.
- Genetic modification of CCR5 offers a potential strategy for HIV-1 therapy.
- Hematopoietic stem/precursor cells (HSPC) are a target for genetic modification.
Purpose of the Study:
- To evaluate the safety and efficacy of CCR5-targeted gene therapy for HIV-1.
- To establish humanized mice as a preclinical model for anti-HIV therapies.
- To assess the generation of HIV-resistant cells from modified HSPC.
Main Methods:
- Transient expression of CCR5-targeted zinc finger nucleases (ZFNs) in human HSPC.
- Transplantation of ZFN-treated HSPC into immunodeficient mice.
- Analysis of human cell engraftment, lineage differentiation, and anti-HIV activity in vivo.
Main Results:
- ZFN modification successfully generated CCR5-negative HSPC.
- Transplanted cells differentiated into mature CD4(+) T cells.
- Humanized mice models demonstrated the potential for anti-HIV activity.
Conclusions:
- CCR5-targeted ZFN therapy is a viable strategy for generating HIV-resistant cells.
- Humanized mice serve as an effective preclinical model for evaluating novel anti-HIV therapies.
- This approach holds promise for the development of future HIV treatments.
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