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A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery

Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endo...

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Autores principales: Choi, Yun-Rak, Collins, Kelsey H., Springer, Luke E., Pferdehirt, Lara, Ross, Alison K., Wu, Chia-Lung, Moutos, Franklin T., Harasymowicz, Natalia S., Brunger, Jonathan M., Pham, Christine T. N., Guilak, Farshid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442875/
https://www.ncbi.nlm.nih.gov/pubmed/34516920
http://dx.doi.org/10.1126/sciadv.abj1414
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author Choi, Yun-Rak
Collins, Kelsey H.
Springer, Luke E.
Pferdehirt, Lara
Ross, Alison K.
Wu, Chia-Lung
Moutos, Franklin T.
Harasymowicz, Natalia S.
Brunger, Jonathan M.
Pham, Christine T. N.
Guilak, Farshid
author_facet Choi, Yun-Rak
Collins, Kelsey H.
Springer, Luke E.
Pferdehirt, Lara
Ross, Alison K.
Wu, Chia-Lung
Moutos, Franklin T.
Harasymowicz, Natalia S.
Brunger, Jonathan M.
Pham, Christine T. N.
Guilak, Farshid
author_sort Choi, Yun-Rak
collection PubMed
description Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endogenous inflammatory cytokines to trigger a proportional therapeutic response. Cells were engineered into cartilaginous constructs that showed rapid activation and recovery in response to inflammation in vitro or in vivo. In the murine K/BxN model of inflammatory arthritis, bioengineered implants significantly mitigated disease severity as measured by joint pain, structural damage, and systemic and local inflammation. Therapeutic implants completely prevented increased pain sensitivity and bone erosions, a feat not achievable by current clinically available disease-modifying drugs. Combination tissue engineering and synthetic biology promises a range of potential applications for treating chronic diseases via custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.
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spelling pubmed-84428752021-09-24 A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery Choi, Yun-Rak Collins, Kelsey H. Springer, Luke E. Pferdehirt, Lara Ross, Alison K. Wu, Chia-Lung Moutos, Franklin T. Harasymowicz, Natalia S. Brunger, Jonathan M. Pham, Christine T. N. Guilak, Farshid Sci Adv Biomedicine and Life Sciences Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endogenous inflammatory cytokines to trigger a proportional therapeutic response. Cells were engineered into cartilaginous constructs that showed rapid activation and recovery in response to inflammation in vitro or in vivo. In the murine K/BxN model of inflammatory arthritis, bioengineered implants significantly mitigated disease severity as measured by joint pain, structural damage, and systemic and local inflammation. Therapeutic implants completely prevented increased pain sensitivity and bone erosions, a feat not achievable by current clinically available disease-modifying drugs. Combination tissue engineering and synthetic biology promises a range of potential applications for treating chronic diseases via custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals. American Association for the Advancement of Science 2021-09-01 /pmc/articles/PMC8442875/ /pubmed/34516920 http://dx.doi.org/10.1126/sciadv.abj1414 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Choi, Yun-Rak
Collins, Kelsey H.
Springer, Luke E.
Pferdehirt, Lara
Ross, Alison K.
Wu, Chia-Lung
Moutos, Franklin T.
Harasymowicz, Natalia S.
Brunger, Jonathan M.
Pham, Christine T. N.
Guilak, Farshid
A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title_full A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title_fullStr A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title_full_unstemmed A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title_short A genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
title_sort genome-engineered bioartificial implant for autoregulated anticytokine drug delivery
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442875/
https://www.ncbi.nlm.nih.gov/pubmed/34516920
http://dx.doi.org/10.1126/sciadv.abj1414
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