The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model
<b>Background/Objectives:</b> Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of int...
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| author | Shuang Luo Hao Jiang Qingwei Li Shiping Yang Xuemei Yu Xiongliang Xu Qing Xie Xiao Ke Qiang Zheng |
| author_facet | Shuang Luo Hao Jiang Qingwei Li Shiping Yang Xuemei Yu Xiongliang Xu Qing Xie Xiao Ke Qiang Zheng |
| author_sort | Shuang Luo |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of intra-articular IL-1Ra injections in reducing OA-associated pain or cartilage degradation. <b>Methods:</b> Sustaining sufficient levels of IL-1Ra within the joints via adeno-associated virus (AAV)-mediated gene therapy presents a promising therapeutic strategy for OA. In this study, we constructed an IL-1Ra expression cassette employing intron insertion in the coding sequence (CDS) region to enhance protein expression levels. Furthermore, we incorporated precisely targeted liver-specific microRNA (miRNA) sequences to specifically downregulate transgene expression within hepatic tissues, thereby ensuring more targeted and controlled regulation of gene expression. <b>Results:</b> A rat model of OA was employed to compare the efficacy of AAV5 and AAV9 for IL-1Ra delivery at both high and low doses. It was observed that low-dose, but not high-dose, AAV9-IL-1Ra resulted in a significant reduction in joint swelling, accompanied by a decrease in the diameter of the affected area and the preservation of biomarkers associated with trabecular bone integrity. <b>Conclusions:</b> These results highlight the great potential of AAV9-IL-1Ra in osteoarthritis therapy, with the promise of achieving long-term improvement through a single intra-articular injection. |
| format | Article |
| id | doaj-art-62e2e0cc9d774962a1ff4088b6454660 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-62e2e0cc9d774962a1ff4088b64546602025-08-20T02:01:20ZengMDPI AGPharmaceutics1999-49232024-11-011612151810.3390/pharmaceutics16121518The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat ModelShuang Luo0Hao Jiang1Qingwei Li2Shiping Yang3Xuemei Yu4Xiongliang Xu5Qing Xie6Xiao Ke7Qiang Zheng8Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, ChinaChengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China<b>Background/Objectives:</b> Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of intra-articular IL-1Ra injections in reducing OA-associated pain or cartilage degradation. <b>Methods:</b> Sustaining sufficient levels of IL-1Ra within the joints via adeno-associated virus (AAV)-mediated gene therapy presents a promising therapeutic strategy for OA. In this study, we constructed an IL-1Ra expression cassette employing intron insertion in the coding sequence (CDS) region to enhance protein expression levels. Furthermore, we incorporated precisely targeted liver-specific microRNA (miRNA) sequences to specifically downregulate transgene expression within hepatic tissues, thereby ensuring more targeted and controlled regulation of gene expression. <b>Results:</b> A rat model of OA was employed to compare the efficacy of AAV5 and AAV9 for IL-1Ra delivery at both high and low doses. It was observed that low-dose, but not high-dose, AAV9-IL-1Ra resulted in a significant reduction in joint swelling, accompanied by a decrease in the diameter of the affected area and the preservation of biomarkers associated with trabecular bone integrity. <b>Conclusions:</b> These results highlight the great potential of AAV9-IL-1Ra in osteoarthritis therapy, with the promise of achieving long-term improvement through a single intra-articular injection.https://www.mdpi.com/1999-4923/16/12/1518osteoarthritisgene therapyadeno-associated virusIL-1Ra |
| spellingShingle | Shuang Luo Hao Jiang Qingwei Li Shiping Yang Xuemei Yu Xiongliang Xu Qing Xie Xiao Ke Qiang Zheng The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model Pharmaceutics osteoarthritis gene therapy adeno-associated virus IL-1Ra |
| title | The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model |
| title_full | The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model |
| title_fullStr | The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model |
| title_full_unstemmed | The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model |
| title_short | The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model |
| title_sort | intra articular delivery of a low dose adeno associated virus il 1 receptor antagonist vector alleviates the progress of arthritis in an osteoarthritis rat model |
| topic | osteoarthritis gene therapy adeno-associated virus IL-1Ra |
| url | https://www.mdpi.com/1999-4923/16/12/1518 |
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