TY - JOUR
T1 - Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs
AU - Brunger, Jonathan M.
AU - Zutshi, Ananya
AU - Willard, Vincent P.
AU - Gersbach, Charles A.
AU - Guilak, Farshid
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/5/9
Y1 - 2017/5/9
N2 - 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.
AB - 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.
KW - CRISPR/Cas9
KW - TNF-α
KW - cartilage tissue engineering
KW - genome editing
KW - osteoarthritis
KW - pro-inflammatory cytokine
KW - regenerative medicine
KW - rheumatoid arthritis
KW - synthetic biology
KW - vaccine
UR - http://www.scopus.com/inward/record.url?scp=85018168916&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2017.03.022
DO - 10.1016/j.stemcr.2017.03.022
M3 - Article
C2 - 28457885
AN - SCOPUS:85018168916
SN - 2213-6711
VL - 8
SP - 1202
EP - 1213
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 5
ER -