Treatment of BPD Using Mimetics of Superoxide Dismutase

描述(由申请人提供)： 对患有呼吸窘迫综合征的早产儿进行氧气浓度升高和呼吸道压力增加。在幸存者中，20%到30%的人患上了一种名为支气管肺发育不良(BPD)的慢性肺部疾病，现在的特点是肺泡化和血管形成不良。超氧阴离子(O2-)和其他自由基引起的组织损伤与BPD的发病机制有关。我们合成了一类新颖的小分子锰(III)卟啉类超氧化物歧化酶(SOD)和过氧化氢酶。这些化合物已被证明在各种氧化应激动物模型中有效。最近的研究表明，静脉注射AEOL 10113可以减少妊娠140d外加10d的BPD婴儿模型的炎症和纤维化。AEOL 10113还促进了BPD接受PRN O2治疗14天的125天妊娠模型中的牙槽骨形成。基于这项初步工作，我们假设：1)有效的抗氧化剂模拟物与最佳剂量的肺部将减少或防止早产儿肺泡化的损害，2)在早产后的头几周内在肺内创造一个更少的环境将对肺发育有长期的好处-永久性地改善肺结构和功能，以及3)BPD是一种复杂的、多因素的疾病，在这种疾病中可能需要多种治疗方法来优化治疗，导致正常的肺结构和功能。因此，我们建议1)使用气雾剂优化肺部给药，以获得最高的治疗效益和较低的毒性风险；2)确定AEOL 10113在125d妊娠、21天随访模型中的剂量-反应关系；3)在125d妊娠模型中评估两种新的抗氧化剂模拟物；4)将125d妊娠模型延长至6个月随访，以显示长期治疗益处；以及5)评估联合治疗的潜在优势。我们认为，在人类临床试验中使用这种低分子催化抗氧化剂的治疗策略应该是可能的，但关键是使用狒狒模型来优化条件并将可能的毒性降至最低。

DESCRIPTION (provided by applicant): Elevated concentrations of oxygen and increased airway pressure are administered to preterm neonates with respiratory distress syndrome. Among the survivors, 20% to 30% develop a form of chronic lung disease called bronchopulmonary dysplasia (BPD) and which is now characterized by poor alveolarization and vascularization. Tissue injury caused by the superoxide anion (O2-) and other free oxygen radicals has been implicated in the pathogenesis of BPD. We have synthesized a class of novel, small Mn(III) porphyrin mimetics of superoxide dismutase (SOD) and catalase. These compounds have been shown to be effective in a variety of animal models of oxidative stress. Recent work has shown that AEOL 10113 by IV infusion decreases inflammation and fibrosis in the 140-day gestation plus 10 days 100% neonatal baboon model of BPD. AEOL 10113 also enhances alveolarization in the 125-day gestation model of BPD receiving PRN O2 for 14 days. Based on this preliminary work we hypothesize that: 1) An effective antioxidant mimetic with optimum dose to the lung will reduce or prevent impairment of alveolarization in premature infants, 2) Creating a more reducing environment in the lung during the first few weeks following premature delivery will have a long term benefit on lung development - permanently improving lung structure and function, and 3) BPD is a complex, multifactoral disease in which multiple therapeutic approaches are likely to be required to optimize therapy and result in normal lung structure and function. We thus propose 1) optimizing lung delivery by use of an aerosol to give highest therapeutic benefit with the lower risk of toxicity, 2) defining the dose-response relationship for AEOL 10113 in the 125-day gestation, 21-day follow-up model, 3) evaluating two new antioxidant mimetics in the 125-day gestation model, 4) extending the 125-day gestation model to a 6-month follow-up to show long term therapeutic benefit, and 5) evaluate the potential advantages of combination therapy. We believe that it should be possible to use this therapeutic strategy of a low molecular catalytic antioxidant in a human clinical trial, but it is critical to use the baboon model to optimize conditions and minimize possible toxicities.