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一项旨在确定 scAAVIL-1ra 在创伤后骨关节炎大型动物模型中最佳剂量的初步研究。

A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis.

机构信息

Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, CO, USA.

Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA.

出版信息

Gene Ther. 2023 Dec;30(12):792-800. doi: 10.1038/s41434-023-00420-2. Epub 2023 Sep 11.

DOI:10.1038/s41434-023-00420-2
PMID:37696981
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10727982/
Abstract

Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 10 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 10 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 10vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA.

摘要

腺相关病毒载体的基因治疗方法已在马创伤后骨关节炎（PTOA）模型中成功测试。由于在已发表的研究中观察到转基因表达水平和不良组织反应的差异，我们试图确定一种安全的治疗剂量，即在发炎和受伤的关节中使用 scAAVIL-1ra，以改善功能结果而没有任何不良事件。scAAVIL-1ra 在关节内以 100 倍的范围给药，并且在整个 10 周研究期间和结束时对马匹进行了评估。观察到 IL-1ra 水平与 PGE 水平下降呈剂量相关增加，所有组均在治疗后 7 天观察到峰值 IL-1ra 浓度。在接受最高病毒剂量 5×10 vg 治疗的关节滑膜中观察到单核细胞的血管周围浸润，但在低剂量关节中不存在。scAAVeqIL-1ra 的第二高剂量 5×10 vg 表现出升高的 IL-1ra 水平，而滑膜中没有任何细胞反应。总之，数据表明，10 倍低剂量的 5×10vg scAAVIL-1ra 将是 PTOA 马模型中的安全治疗剂量。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/bc777ce7cd9c/41434_2023_420_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/22d26fd601a5/41434_2023_420_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/3002ff1f01eb/41434_2023_420_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/2a53316379bf/41434_2023_420_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/0de9d814102e/41434_2023_420_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/ebc217720b12/41434_2023_420_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/20e37b5e3299/41434_2023_420_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/bc777ce7cd9c/41434_2023_420_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/22d26fd601a5/41434_2023_420_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/3002ff1f01eb/41434_2023_420_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/2a53316379bf/41434_2023_420_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/0de9d814102e/41434_2023_420_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/ebc217720b12/41434_2023_420_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/20e37b5e3299/41434_2023_420_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2023/10727982/bc777ce7cd9c/41434_2023_420_Fig7_HTML.jpg

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