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Stem Cell Reports. 2017 May 9;8(5):1202-1213. doi: 10.1016/j.stemcr.2017.03.022. Epub 2017 Apr 27.

Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs.

Author information

1
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
2
Cytex Therapeutics, Inc., Durham, NC 27705, USA.
3
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
4
Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Cytex Therapeutics, Inc., Durham, NC 27705, USA; Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA; Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA. Electronic address: guilak@wustl.edu.

Abstract

Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases.

KEYWORDS:

CRISPR/Cas9; TNF-α; cartilage tissue engineering; genome editing; osteoarthritis; pro-inflammatory cytokine; regenerative medicine; rheumatoid arthritis; synthetic biology; vaccine

PMID:
28457885
PMCID:
PMC5425682
DOI:
10.1016/j.stemcr.2017.03.022
[Indexed for MEDLINE]
Free PMC Article

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