Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure
Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure
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DOI：
10.1016/j.pupt.2012.12.005
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发表时间：
2013-04-01
影响因子：
3.2
通讯作者：
Garn, Holger
中科院分区：
文献类型：
--
作者：
Fuhst, Rainer;Runge, Frank;Garn, Holger
DNAzymes是单链催化DNA分子，可以结合和切割靶mRNA分子中的特定序列。它们作为新型治疗剂的潜力已在多种疾病模型中得到证实。然而，目前还没有研究详细阐述它们的毒理学和安全药理学特征。在这里，我们描述了吸入hgd40的详细毒理学分析，hgd40是一种用于治疗过敏性支气管哮喘的gata -3特异性DNAzyme。分析了啮齿动物和非啮齿动物的亚急性毒性、免疫毒性、呼吸、心血管和中枢神经系统安全性药理学，并评估了人外周血的遗传毒性。总的来说，通过气溶胶吸入或缓慢静脉输注给药时，hgd40的耐受性非常好。在吸入最高剂量hgd40的大鼠的肺中只观察到边缘可逆的组织病理学改变。变化包括轻微的单核细胞浸润和肺泡组织细胞增生，支气管相关淋巴组织中度增生。在狗身上没有观察到局部或全身的不良反应。未观察到与化合物相关的呼吸、心血管或中枢神经系统不良事件。唯一相关的免疫学结果是支气管肺泡灌洗液中白细胞介素-10和干扰素- γ水平有非常轻微的剂量依赖性变化。综上所述，这些结果支持通过吸入直接递送DNAzyme用于治疗呼吸系统疾病。(c) 2012 Elsevier Ltd.版权所有。
DNAzymes are single-stranded catalytic DNA molecules that bind and cleave specific sequences in a target mRNA molecule. Their potential as novel therapeutic agents has been demonstrated in a variety of disease models. However, no studies have yet addressed their toxicology and safety pharmacology profiles in detail. Here we describe a detailed toxicological analysis of inhaled hgd40, a GATA-3-specific DNAzyme designed for the treatment of allergic bronchial asthma. Subacute toxicity, immunotoxicity, and respiratory, cardiovascular, and CNS safety pharmacology were analyzed in rodents and non-rodents, and genotoxicity was assessed in human peripheral blood. Overall, hgd40 was very well tolerated when delivered by aerosol inhalation or slow intravenous infusion. Only marginal reversible histopathological changes were observed in the lungs of rats receiving the highest dose of inhaled hgd40. The changes consisted of slight mononuclear cell infiltration and alveolar histiocytosis, and moderate hyperplasia of bronchus-associated lymphoid tissue. No local or systemic adverse effects were observed in dogs. No compound-related respiratory, cardiovascular, or CNS adverse events were observed. The only relevant immunological findings were very slight dose-dependent changes in interleukin-10 and interferon-gamma levels in bronchoalveolar lavage fluid. Taken together, these results support direct delivery of a DNAzyme via inhalation for the treatment of respiratory disease. (c) 2012 Elsevier Ltd. All rights reserved.