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给予高浓度的氧气和增加的气道压力。在幸存者中，20%至30%发展成一种称为支气管肺发育不良（BPD）的慢性肺病，其特征是肺泡化和血管化不良。超氧阴离子（O2-）和其他氧自由基引起的组织损伤与BPD的发病机制有关。我们已经合成了一类新的，小锰（III）卟啉模拟超氧化物歧化酶（SOD）和过氧化氢酶。这些化合物已被证明是有效的，在各种动物模型的氧化应激。最近的研究表明，通过IV输注AEOL 10113减少了140天妊娠加10天100%新生狒狒BPD模型中的炎症和纤维化。AEOL 10113还增强了接受PRN O2 14天的BPD 125天妊娠模型中的肺泡形成。基于这一初步工作，我们假设：1）对肺具有最佳剂量的有效的抗氧化剂模拟物将减少或预防早产儿肺泡化的损害，2）在早产后的前几周期间在肺中创造更还原的环境将对肺发育具有长期益处-永久改善肺结构和功能，以及3）BPD是一种复合物，多因素疾病，可能需要多种治疗方法来优化治疗并导致正常的肺结构和功能。因此，我们提出1）通过使用气雾剂优化肺部递送以提供最高的治疗益处和较低的毒性风险，2）在125天妊娠、21天随访模型中定义AEOL 10113的剂量-反应关系，3）在125天妊娠模型中评估两种新的抗氧化剂模拟物，4）将125天妊娠模型扩展至6个月随访以显示长期治疗益处，和5）评估联合治疗的潜在优势。我们认为，应该有可能在人体临床试验中使用这种低分子催化抗氧化剂的治疗策略，但关键是使用狒狒模型来优化条件并最大限度地减少可能的毒性。

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.