2. Academic Validation
  3. Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis

Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis

  • Ann Rheum Dis. 2024 Sep 4:ard-2024-225565. doi: 10.1136/ard-2024-225565.
Fang Qiu # 1 2,  Duoli Xie # 1 2,  Hongzhen Chen 1,  Zhuqian Wang 1 2,  Jie Huang 1 2,  Chunhao Cao 1 2,  Yiying Liang 3,  Xu Yang 4,  Dong-Yi He 5,  Xuekun Fu 6,  Aiping Lu 7 8 9,  Chao Liang 6 2 10
Affiliations

Affiliations

  • 1 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
  • 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
  • 3 LingGene Biotech Co., Ltd, Shenzhen, China.
  • 4 Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China fuxk@mail.sustech.edu.cn aipinglu@hkbu.edu.hk liangc@sustech.edu.cn.
  • 7 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China fuxk@mail.sustech.edu.cn aipinglu@hkbu.edu.hk liangc@sustech.edu.cn.
  • 8 Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China.
  • 9 Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 10 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • # Contributed equally.
PMID: 39237134 DOI: 10.1136/ard-2024-225565
Abstract

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease characterised by aggressive fibroblast-like synoviocytes (FLSs). Very few RA patients-derived FLSs (RA-FLSs)-specific surface signatures have been identified, and there is currently no approved targeted therapy for RA-FLSs. This study aimed to screen therapeutic Aptamers with cell-targeting and cytotoxic properties against RA-FLSs and to uncover the molecular targets and mechanism of action of the screened Aptamers.

Methods: We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic Aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened Aptamers were determined by pull-down assays and RNA Sequencing. The therapeutic efficacy of the screened Aptamers was examined in arthritic mouse models.

Results: We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models.

Conclusions: CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic Aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.

Keywords

Arthritis, Experimental; Fibroblasts; Inflammation; Rheumatoid Arthritis; Therapeutics.

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