L-arginine as a therapy in severe asthma

描述（由申请人提供）：哮喘是一种进行性炎性气道疾病，在许多严重影响的成年人中导致气道结构性改变和衰弱症状。我们需要能够负担得起的新型治疗药物，可以减少对类固醇的依赖，并且可以提高生活质量。这项临床和机制研究有可能影响一部分成人严重哮喘患者的治疗，并进一步了解哮喘患者气道中l -精氨酸代谢和NO生物学的机制。在标准药物治疗对照不良的人群中开展临床试验；该策略将探讨l -精氨酸对接受标准护理药物治疗的患者是否有效。在使用动物模型的研究中，我们和其他人已经表明，通过补充l -精氨酸或抑制精氨酸酶来增加NO水平的干预措施，可以减少过敏性气道炎症和高反应性——哮喘的两个特征。总的来说，我们假设有反应的成人严重哮喘患者将从补充l -精氨酸治疗中获得临床益处，这些患者的呼出NO浓度（<20 ppb）较低，气道上皮细胞中的NOS2/Arg1 mRNA和蛋白质比例高于无反应的患者。我们的目标是：1)验证呼气NO浓度<20 ppb的未控制的成人严重哮喘患者在3个月内接受l -精氨酸治疗比接受FeNO治疗的患者哮喘发作次数更少的假设；2)确定l -精氨酸影响严重哮喘受试者气道上皮细胞培养物中NOS和精氨酸酶调节的机制。3)验证吸入l -精氨酸纳米颗粒载体制剂在较低剂量下比全身给予l -精氨酸能减少气道炎症、气道高反应性和气道纤维化的假设。本研究的主要影响将是确定将受益于补充l -精氨酸治疗的成人严重哮喘队列。我们的最终目标是开发新的治疗药物，以更好地治疗成人重症哮喘患者。

DESCRIPTION (provided by applicant): Asthma is a progressive inflammatory airways disease that leads to structural airway changes and debilitating symptoms in many severely affected adults. We need novel therapeutic agents that are affordable, can decrease the reliance on steroids, and can improve quality of life. This clinical and mechanistic study has the potential to impact treatment of a subset of adult severe asthmatics and to further our understanding of the mechanisms of L-arginine metabolism and NO biology in the airways of asthmatics. We will pursue a clinical trial in subjects not well controlled on standard drug therapy; this strategy will address whether L-arginine is efficacious in patients receiving standard of care medications. In studies using animal models, we and others have shown that interventions that augment NO levels, through either supplementation of L-arginine or inhibition of arginase, decrease allergic airway inflammation and hyperresponsiveness-the two hallmarks of asthma. Overall, we hypothesize that a "responder" subset of adult severe asthma patients will derive clinical benefit from supplemental L-arginine therapy and that these patients will have a lower exhaled NO concentrations (<20 ppb) and a higher NOS2/Arg1 mRNA and protein ratio in their airway epithelial cells than "non-responders." We aim to: 1) test the hypothesis that uncontrolled, adult severe asthma patients with exhaled breath NO concentrations <20 ppb will have fewer asthma exacerbations over 3 months when treated with L-arginine compared to patients with FeNO > 25, 2) determine the mechanisms by which L-arginine affects the regulation of NOS and arginase enzymes in primary airway epithelial cell cultures from severe asthmatic subjects, and 3) test the hypothesis that inhaled nanoparticle carrier formulations of L-arginine will decrease airway inflammation, airway hyperresponsiveness, and airway fibrosis at lower doses than systemically administered L-arginine. The major impact of our study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. Our ultimate goal is to develop novel therapeutic agents to treat adult severe asthma patients better.