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A Genome-engineered Bioartificial Implant for Autoregulated Anti-Cytokine Drug Delivery

Authors
 Yun-Rak Choi  ;  Kelsey H. Collins  ;  Luke E. Springer  ;  Lara Pferdehirt  ;  Alison K. Ross  ;  Chia-Lung Wu  ;  Franklin T. Moutos  ;  Natalia S. Harasymowicz  ;  Jonathan M. Brunger  ;  Christine T.N. Pham  ;  Farshid Guilak 
Citation
 SCIENCE ADVANCES, Vol.7 : eabj1414, 2021-09 
Journal Title
SCIENCE ADVANCES
Issue Date
2021-09
Keywords
Regenerative medicine ; synthetic biology ; cell therapy ; stem cell ; tissue engineering ; inflammation ; arthritis
Abstract
Biologic drug therapies are effective treatments for autoimmune diseases such as rheumatoid arthritis (RA) but may cause significant adverse effects, as they are administered continuously at high doses that can suppress the immune system. Using CRISPR-Cas9 genome editing, we engineered stem cells containing a synthetic gene circuit expressing biologic drugs to antagonize interleukin-1 (IL-1) or tumor necrosis factor (TNF) in an autoregulated, feedback-controlled manner in response to activation of the endogenous chemokine (C-C) motif ligand 2 (Ccl2) promoter. To test this approach in vivo, cells were tissue-engineered into a stable cartilaginous construct and implanted subcutaneously in mice with inflammatory arthritis. Bioengineered anti-cytokine implants mitigated arthritis severity as measured by joint pain, structural damage, and systemic and local inflammation. The coupling of synthetic biology with tissue engineering promises a range of potential applications for treating chronic diseases using custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.

Despite advances in the development of disease-modifying anti-rheumatic biologic drugs, approximately 40% of patients with rheumatoid arthritis (RA) fail to respond to treatment1. While the severity of RA fluctuates, biologic drugs are administered continuously at high concentrations, predisposing patients to significant adverse effects, such as increased risk of infection2. The development of therapeutics that can sense and respond to dynamically changing levels of endogenous inflammatory mediators may improve efficacy while mitigating the side effects of continuous biologic delivery3-5. Here, we used CRISPR-Cas9 genome engineering6,7 to create a self-regulating gene circuit in induced pluripotent stem cells (iPSCs). These cells were designed to produce anti-cytokine biologic drugs in response to inflammatory signals such as interleukin-1 (IL-1) or tumor necrosis factor α (TNF-α) by transcribing their biologic inhibitors in a feedback-controlled manner3, driven by the promoter of the chemokine (C-C) motif ligand 2 (Ccl2) (Fig. 1)8. For delivery in vivo, iPSCs were differentiated into a cartilaginous implant and engineered into a cartilaginous implant that maintains the cells in a stable subcutaneous depot, allowing for sensing of systemic inflammation as well as free diffusion of the biologic drugs into the circulation. We demonstrated that these bioengineered implants provide dynamic, autoregulated delivery of anti-cytokine biologic drugs that mitigate structural damage, pain, and inflammation in a murine model of arthritis.
Files in This Item:
T202103873.pdf Download
DOI
10.1101/535609
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
Yonsei Authors
Choi, Yun Rak(최윤락)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184849
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