Amphoteric Liposomes Enable Systemic Antigen-Presenting Cell-Directed Delivery of CD40 Antisense and Are Therapeutically Effective in Experimental Arthritis
Amphoteric Liposomes Enable Systemic Antigen-Presenting Cell-Directed Delivery of CD40 Antisense and Are Therapeutically Effective in Experimental Arthritis
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DOI：
10.1002/art.24434
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发表时间：
2009-04-01
影响因子：
--
通讯作者：
Panzner, Steffen
中科院分区：
文献类型：
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作者：
Andreakos, Evangelos;Rauchhaus, Una;Panzner, Steffen
客观的。寡核苷酸介导的RNA干扰是沉默与炎症性疾病发病机制相关的基因的有效方法，但该技术的体内应用需要有效递送至免疫细胞和/或炎症部位。本研究的目的是开发一种新的载体系统来介导寡核苷酸对类风湿性关节炎（RA）关节的全身给药，并开发一种基于反义寡核苷酸（ASO）的方法来干扰 RA 实验模型中的 CD40-CD154 相互作用。方法。开发了一种具有两性特性的新型脂质体载体，称为 Nov038，并评估了其系统递送针对 CD40 (CD40-ASO) 的 ASO 的能力。用 Nov038 封装的 CD40-ASO 治疗患有胶原诱导关节炎的雄性 DBA/1 小鼠，并评估治疗对疾病活动的各种参数的影响，包括临床评分、爪肿胀、淋巴结反应和关节中炎症细胞因子的产生。结果。 Nov038 耐受性良好，没有免疫刺激作用，并且能有效介导全身性寡核苷酸递送至炎症部位。在患有胶原诱导关节炎的小鼠中，Nov038 能够进行 CD40-ASO 的治疗性给药并改善已确定的疾病，而在没有辅助的情况下 CD40-ASO 无效，并且抗肿瘤坏死因子 a（抗 TNF α）治疗在此模型中效果较差。 Nov038/CD40-ASO 的功效归因于其对单核细胞/巨噬细胞和骨髓树突状细胞 (DC) 的趋向性，导致 CD40 快速下调、抑制 DC 抗原呈递、减少胶原蛋白特异性 T 细胞反应，以及降低关节炎关节中 TNF α、白细胞介素 6 (IL-6) 和 IL-17 的水平。结论。两性脂质体代表了一种用于全身性和抗原呈递细胞靶向寡核苷酸递送的新型载体概念，具有临床适用性和众多潜在应用，包括体内靶标验证和炎症性疾病治疗。此外，Nov038/CD40-ASO 是干扰 CD40-CD40L 相互作用的单克隆抗体方法的有效替代方法。
Objective. Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO)-based approach to interfere with CD40-CD154 interactions in an experimental model of RA.Methods. A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40-ASO). Male DBA/1 mice with collagen-induced arthritis were treated with Nov038-encapsulated CD40-ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed.Results. Nov038 was well tolerated, devoid of immune-stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen-induced arthritis, Nov038 enabled the therapeutic administration of CD40-ASO and improved established disease, while unassisted CD40-ASO was ineffective, and anti-tumor necrosis factor a (anti-TNF alpha) treatment was less effective in this model. Nov038/CD40-ASO efficacy was attributed to its tropism for monocyte/macrophages and myeloid dendritic cells (DCs), resulting in rapid down-regulation of CD40, inhibition of DC antigen presentation, and reduction in collagen-specific T cell responses, as well as decreased levels of TNF alpha, interleukin-6 (IL-6), and IL-17 in arthritic joints.Conclusion. Amphoteric liposomes represent a novel carrier concept for systemic and antigen-presenting cell-targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40-ASO constitutes a potent alternative to monoclonal antibody-based approaches for interfering with CD40-CD40L interactions.