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Zhang S, Zhou M, Shao C, Zhao Y, Liu M, Ni L, Bao Z, Zhang Q, Zhang T, Luo Q, Qu J, Xu Z, Zuo W. Autologous P63+ lung progenitor cell transplantation in idiopathic pulmonary fibrosis: a phase 1 clinical trial. eLife 2025; 13:RP102451. [PMID: 40036154 PMCID: PMC11879106 DOI: 10.7554/elife.102451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025] Open
Abstract
Background In idiopathic pulmonary fibrosis (IPF) patients, alveolar architectures are lost and gas transfer function would decline, which cannot be rescued by conventional anti-fibrotic therapy. P63+ lung basal progenitor cells are reported to have potential to repair damaged lung epithelium in animal models, which need further investigation in clinical trials. Methods We cloned and expanded P63+ progenitor cells from IPF patients to manufacture cell product REGEND001, which were further characterized by morphology and single-cell transcriptomic analysis. Subsequently, an open-label, dose-escalation autologous progenitor cell transplantation clinical trial was conducted. We treated 12 patients with ascending doses of cells: 0.6x, 1x, 2x and 3.3x106 cells/kg bodyweight. The primary outcome was the incidence and severity of cell therapy-related adverse events (AEs); secondary outcome included other safety and efficacy evaluations. Results P63+ basal progenitor cell was safe and tolerated at all doses, with no dose-limiting toxicity or cell therapy-related severe adverse events observed. Patients in three higher dose groups showed significant improvement of lung gas transfer function as well as exercise ability. Resolution of honeycomb lesion was observed in patients of higher dose groups. Conclusions REGEND001 has high safety profile and meanwhile encourages further efficacy exploration in IPF patients. Funding National High Level Hospital Clinical Research Funding (2022-PUMCH-B-108), National Key Research and Development Plan (2024YFA1108900, 2024YFA1108500), Jiangsu Province Science and Technology Special Project Funding (BE2023727), National Biopharmaceutical Technology Research Project Funding (NCTIB2023XB01011), Non-profit Central Research Institute Fund of Chinese Academy of Medical Science (2020-PT320-005), and Regend Therapeutics. Clinical trial number Chinese clinical trial registry: CTR20210349.
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Affiliation(s)
- Shiyu Zhang
- Shanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
- Tongji Stem Cell Center, Tongji UniversityShanghaiChina
| | - Min Zhou
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chi Shao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Yu Zhao
- Shanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
- Tongji Stem Cell Center, Tongji UniversityShanghaiChina
| | - Mingzhe Liu
- Shanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
- Tongji Stem Cell Center, Tongji UniversityShanghaiChina
| | - Lei Ni
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zhiyao Bao
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qiurui Zhang
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ting Zhang
- Super Organ R&D Center, Regend TherapeuticsShanghaiChina
| | - Qun Luo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Jieming Qu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Zuojun Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Wei Zuo
- Shanghai East Hospital, School of Medicine, Tongji UniversityShanghaiChina
- Tongji Stem Cell Center, Tongji UniversityShanghaiChina
- Super Organ R&D Center, Regend TherapeuticsShanghaiChina
- Kiangnan Stem Cell InstituteZhejiangChina
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Ding C, Guo Z, Liao Q, Zuo R, He J, Ye Z, Chen W. Network Pharmacology and Machine Learning Reveal Salidroside's Mechanisms in Idiopathic Pulmonary Fibrosis Treatment. J Inflamm Res 2024; 17:9453-9467. [PMID: 39600682 PMCID: PMC11590657 DOI: 10.2147/jir.s493171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024] Open
Abstract
Purpose Idiopathic pulmonary fibrosis (IPF) is an irreversible respiratory disease. In this study, we evaluated the efficacy of salidroside (SAL), the main component of Rhodiola rosea, in treating IPF. Methods The pharmacological effects of SAL against epithelial-mesenchymal transition (EMT) and IPF were assessed through in vivo and in vitro experiments. Targets for SAL in treating IPF were identified from various databases and a PPI network was constructed. Functional analyses of target genes were performed using GO, KEGG, DO, and GSEA. Core target genes were identified using LASSO logistic regression and support vector machine (SVM) analysis, followed by molecular docking simulations. Predicted targets and pathways were validated through Western blotting, qRT-PCR, and IHC. Results Our results demonstrated that SAL ameliorated alveolar epithelial cells (AECs) EMT and mitigated bleomycin -induced pulmonary fibrosis. Through network pharmacology, we identified 74 targets for SAL in the treatment of IPF (PFDR<0.05) and analyzed their biological functions. Based on these findings, we further applied machine learning techniques to narrow down 9 core targets (PFDR<0.05). Integrating the results from molecular docking, KEGG, and GSEA analyses, we selected three key targets-IGF1, hypoxia-inducible factor 1-alpha (HIF-1α), and MAPK (PFDR<0.05)-for further investigation. Our study revealed that SAL inhibits the IGF1 signaling pathway, thereby improving AECs senescence and cell cycle arrest. By inhibiting the HIF-1α pathway, SAL alleviates endoplasmic reticulum stress and reduces intracellular ROS accumulation. Moreover, SAL suppresses the activation of the MAPK signaling pathway, leading to a decrease in inflammation markers in AECs and lung tissue. Conclusion Experimental results suggest that SAL effectively ameliorates BLM-induced EMT and IPF, likely through the inhibition of IGF1, HIF-1α, and MAPK signaling pathways. This study holds potential translational prospects and may provide new perspectives and insights for the use of traditional Chinese medicine in the treatment of IPF.
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Affiliation(s)
- Chenchun Ding
- Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Zhenzhen Guo
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Quan Liao
- Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Renjie Zuo
- Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Junjie He
- Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Ziwei Ye
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
| | - Weibin Chen
- Department of Thoracic Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of China
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Antoniou KM, Tsitoura E, Vasarmidi E, Symvoulakis EK, Aidinis V, Tzilas V, Tzouvelekis A, Bouros D. Precision medicine in idiopathic pulmonary fibrosis therapy: From translational research to patient-centered care. Curr Opin Pharmacol 2021; 57:71-80. [PMID: 33556824 DOI: 10.1016/j.coph.2020.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic chronic lung disease affecting predominantly older adults, with a history of smoking. The current model of disease natural course is that recurrent injury of the alveolar epithelium in the context of advanced aging/cellular senescence is followed by defective re-epithelialization and scar tissue formation. Currently, two drugs, nintedanib and pirfenidone, that modify disease progression have been approved worldwide for the treatment of IPF. However, despite treatment, patients with IPF are not cured, and eventually, disease advances in most treated patients. Enhancing biogenomic and metabolic research output, its translation into clinical precision and optimal service delivery through patient-centeredness are key elements to support effective IPF care. In this review, we summarize therapeutic options currently investigated for IPF based on the major pathogenetic pathways and molecular targets that drive pulmonary fibrosis.
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Affiliation(s)
- Katerina M Antoniou
- Molecular & Cellular Pneumonology Laboratory, Department of Respiratory Medicine, Faculty of Medicine, University of Crete, Greece.
| | - Eliza Tsitoura
- Molecular & Cellular Pneumonology Laboratory, Department of Respiratory Medicine, Faculty of Medicine, University of Crete, Greece
| | - Eirini Vasarmidi
- Molecular & Cellular Pneumonology Laboratory, Department of Respiratory Medicine, Faculty of Medicine, University of Crete, Greece
| | | | - Vassilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vassilis Tzilas
- Center for Diseases of the Chest, Athens Medical Center, Athens, Greece
| | | | - Demosthenes Bouros
- Center for Diseases of the Chest, Athens Medical Center, Athens, Greece; Medical School, National and Kapodistrian University of Athens, Greece
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Ji HL, Liu C, Zhao RZ. Stem cell therapy for COVID-19 and other respiratory diseases: Global trends of clinical trials. World J Stem Cells 2020; 12:471-480. [PMID: 32742564 PMCID: PMC7360994 DOI: 10.4252/wjsc.v12.i6.471] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 05/17/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.
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Affiliation(s)
- Hong-Long Ji
- Department of Cellular and Molecular Biology, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
- Texas Lung Injury Institute, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
| | - Cong Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen 518000, Guangdong Province, China
| | - Run-Zhen Zhao
- Department of Cellular and Molecular Biology, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
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Immune Checkpoints as Promising Targets for the Treatment of Idiopathic Pulmonary Fibrosis? J Clin Med 2019; 8:jcm8101547. [PMID: 31561518 PMCID: PMC6833050 DOI: 10.3390/jcm8101547] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/16/2019] [Accepted: 09/24/2019] [Indexed: 12/21/2022] Open
Abstract
Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedanib in IPF, in combination with the recent notion that IPF shares several pathogenic pathways with cancer, raised hope that immune checkpoint inhibitors, the novel revolutionary anticancer agents, could also be the eagerly awaited ground-breaking and unconventional novel treatment modality limiting IPF-related morbidity/mortality. In the current review, we analyse the available literature on immune checkpoint proteins in IPF to explore whether immune checkpoint inhibition may be as promising in IPF as it is in cancer. We conclude that despite several promising papers showing that inhibiting specific immune checkpoint proteins limits pulmonary fibrosis, overall the data seem to argue against a general role of immune checkpoint inhibition in IPF and suggest that only PD-1/PD-L1 inhibition may be beneficial.
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