CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis

Yuhong Huang; Zhuqian Wang; Chuanxin Zhong; Hongzhen Chen; Xinxin Chen; Chunhao Cao; Fang Qiu; Duoli Xie; Jin Li; Jie Li; Xu Yang; Aiping Lu; Xuekun Fu; Chao Liang

doi:10.59717/j.xinn-med.2024.100050

The Innovation Medicine > 2024 Vol. 2 > No. 1 > 100050

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CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis

1.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
2.
Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
3.
Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China
4.
Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen 518055, China
5.
Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
6.
Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou 510006, China
7.
Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
8.
State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
9.
These authors contributed equally

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Corresponding authors: aipinglu@hkbu.edu.hk (A.L.); fuxk@mail.sustech.edu.cn (X.F.); liangc@sustech.edu.cn (C.L.)
Received Date: 24 July 2023

Accepted Date: 23 December 2023

Published Online: 05 February 2024

The Innovation Medicine 2(1), https://doi.org/10.59717/j.xinn-med.2024.100050 | Cite this article

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GRAPHICAL ABSTRACT

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PUBLIC SUMMARY
1. The Elite macrophages (MΦs) are constructed using CRISPRa-based genome editing.
  
  The Elite MΦs possess powerful anti-inflammatory capability.
  
  The Elite MΦs display enhanced chemotactic characteristics.
  
  The Elite MΦs relieve arthritis in mouse models of Rheumatoid Arthritis.

ABSTRACT

ABSTRACT

Rheumatoid arthritis (RA) is a poly-articular systemic autoimmune disorder characterized by infiltration of immune cells, synovial hyperplasia and joint destruction. Macrophages (MΦs) can polarize into either pro-inflammatory M1 or anti-inflammatory M2 phenotype in response to different environmental signals. In RA, MΦs are prone to polarize into the M1 phenotype. Reprogramming MΦs has shown promise in treating diseases, e.g., the chimeric antigen receptor-MΦ (CAR-M)-based adoptive immunotherapy. Interleukin-10 (IL-10) is one of the pivotal factors for M2 polarization. Clustered regularly interspaced short palindromic repeats-based transcriptional activation (CRISPRa) harnesses the native machinery in cells to enable a quick and efficient increase of endogenous gene expression. Here, we combined a CRISPRa system with adoptive cell therapy to construct engineered lastingly interleukin-ten (IL-10) expressed MΦs (Elite MΦs). The Elite MΦs possessed powerful anti-inflammatory capability and represented a pre-activated state of M2 MΦs in vitro. The Elite MΦs were more susceptible to an M2 inducer while resistant to M1 inducers. The Elite MΦs displayed enhanced chemotactic characteristics, leading to accumulated in vivo distribution at inflamed sites. Systemic administration of the Elite MΦs relieved inflammation, synovial hyperplasia and joint destruction in mouse models of RA. The Elite MΦs constructed by CRISPRa hold promise for addressing the current unmet medical need in RA.

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Huang Y., Wang Z., Zhong C., et al., (2024). CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis. The Innovation Medicine 2(1): 100050. https://doi.org/10.59717/j.xinn-med.2024.100050

Huang Y., Wang Z., Zhong C., et al., (2024). CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis. The Innovation Medicine 2(1): 100050. https://doi.org/10.59717/j.xinn-med.2024.100050

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CRISPRa engineered Elite macrophages enable adoptive cell therapy for rheumatoid arthritis

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