Development of an oxygen delivery biotherapeutic for the preservation of myocardial function during pediatric cardiopulmonary bypass

开发用于在儿科体外循环期间保存心肌功能的氧气输送生物治疗药物

• 批准号: 9256317
• 负责人: JEFFREY R FINEMAN
• 金额: $ 29.84万
• 依托单位: OMNIOX, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256317
• 关键词: Address; Animal Model; Attenuated; Biochemical; Biological Preservation; Biological Response Modifier Therapy; Birth; Blood Vessels; Blood flow; Brain Ischemia; Bypass; CHD1 gene; California; Cardiac; Cardiac Surgery procedures; Cardioplegic Solutions; Cardiopulmonary; Cardiopulmonary Bypass; Caring; Carrier Proteins; Cell Death; Cerebrum; Child; Childhood; Clinical; Clinical Trials; Closure by clamp; Congenital Heart Defects; Consent Forms; Data; Defect; Development; Disease; Disease model; Dose; Endothelin; Environment; Formulation; Free Radicals; Functional disorder; Heart; Hepatic; High Pressure Liquid Chromatography; Hypoxia; Infant; Injury; Kidney; Kidney Failure; Lead; Left; Liver; Lung; Measures; Medical; Modeling; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Neonatal; Neurologic; Neurologic Deficit; Newborn Infant; Nitric Oxide; Operative Surgical Procedures; Organ; Oxygen; Pamphlets; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Postoperative Period; Preparation; Process; Production; Proteins; Research Personnel; Safety; San Francisco; Shunt Device; Small Business Innovation Research Grant; Surgeon; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; Universities; analytical method; body system; clinically relevant; congenital heart disorder; deprivation; design; efficacy testing; experience; heart function; hemodynamics; hypoperfusion; improved; inhaled nitric oxide; manufacturing process; method development; neonatal patient; neonate; novel; pediatric patients; persistent pulmonary hypertension; preclinical development; preclinical study; prevent; protective effect; protein degradation; repaired; response; stem; therapeutic candidate; time use; translational approach

1. PROJECT SUMMARY/ABSTRACT Omniox is developing a unique oxygen delivery protein, OMX, as a treatment to preserve myocardial and peripheral organ function and significantly reduce morbidity after neonatal cardiopulmonary bypass (CPB) during surgical correction of congenital heart disease (CHD). Of the ~40,000 children born annually with CHD, ~10,000 require urgent surgery to repair heart defects1, 2. Up to 60% of infants who undergo CPB will experience post-operative complications that can result in peripheral organ dysfunction and long-term neurological deficits3-15. A critical driver of the myocardial and peripheral organ tissue damage is oxygen deprivation, or hypoxia3-15. However, there are no current or promising therapeutic approaches that target hypoxia during CPB surgery to stem or alleviate its damaging downstream effects. Omniox' lead therapeutic candidate, OMX, is designed to restore physiologic oxygen levels in hypoxic tissues. Thus, OMX has the potential to address a high unmet need of preserving myocardial function and improving morbidity associated with neonatal CPB surgery. Together with our collaborators, neonatal and pediatric care intensivists Drs. Fineman and Maltepe at the University of California, San Francisco (UCSF), we have demonstrated that OMX attenuates hypoxia- induced myocardial dysfunction in lambs. Furthermore, our preliminary data demonstrate that OMX: 1) restores physiologic oxygen levels specifically in oxygen-deprived tissues; 2) prevents hypoxia-induced cell death after brain ischemia; 3) is stable, safe, and well tolerated in multiple species; and 4) does not increase free radical production or scavenge nitric oxide. The objective of this Fast-Track SBIR Phase I/II proposal is to complete preclinical development of OMX as a novel biologic for the treatment of neonates undergoing CPB by demonstrating its therapeutic utility in oxygenating hypoxic tissue and preserving myocardial and peripheral organ function. We propose to 1) demonstrate OMX preserves myocardial and peripheral organ function during and after CPB in intact newborn lambs (Phase I), then 2) demonstrate OMX' efficacy in a clinically relevant neonatal lamb CHD model undergoing CPB (Phase II). These data will inform an IND application for a neonatal and pediatric clinical trial. Pending good safety and efficacy data in neonatal and pediatric patients undergoing CPB, Omniox plans to expand OMX use to other pediatric indications in which hypoxia drives disease pathology such as persistent pulmonary hypertension in neonates16, 17 and birth asphyxia18-22. Omniox, Inc. ©2016 Confidential – Not for Distribution

1.项目总结/摘要 Omniox正在开发一种独特的氧传递蛋白OMX，作为一种保护心肌的治疗方法 和外周器官功能，显著降低新生儿心肺术后的发病率 先天性心脏病(CHD)手术中的体外循环(CPB)。在出生的约40,000名儿童中 每年有大约10,000名冠心病患者需要紧急手术来修复心脏缺陷1，2。高达60%的婴儿患有心脏病 接受体外循环将经历手术后并发症，可能导致周围器官功能障碍和 长期神经缺陷3-15岁。 心肌和外周器官组织损伤的关键驱动因素是缺氧，或缺氧3-15。 然而，目前或有希望的治疗方法是在CPB手术期间针对缺氧来 阻止或减轻其破坏性的下游影响。Omniox的主要候选治疗药物OMX是设计的 以恢复低氧组织中的生理性氧水平。因此，OMX具有解决高 与新生儿体外循环手术相关的保护心肌功能和改善发病率的需求尚未得到满足。 与我们的合作者一起，新生儿和儿科护理强化专家Fineman博士和Maltepe博士在 加州大学旧金山分校(UCSF)，我们已经证明了OMX可以缓解缺氧- 致羔羊心肌功能障碍。此外，我们的初步数据表明，OMX： 1)恢复特别是缺氧组织的生理性氧水平； 2)防止脑缺血后缺氧诱导的细胞死亡； 3)在多种物种中稳定、安全和耐受性良好；以及 4)不增加自由基的产生或清除一氧化氮。 这项快速通道SBIR I/II阶段计划的目标是完成OMX作为一种 新生儿体外循环治疗的新生物通过展示其治疗有效性 给缺氧组织充氧，保护心肌和外周器官功能。我们建议1) OMX对完好新生儿体外循环期间和术后心肌和外周器官功能的保护作用 Lambs(I期)，然后2)在临床相关的新生儿Lamb CHD模型中展示OMX的疗效 正在进行CPB(第二阶段)。这些数据将为IND申请新生儿和儿科临床试验提供依据。 在对接受CPB的新生儿和儿童患者进行良好的安全性和有效性数据之前，Omniox计划 将OMX的使用扩展到其他儿科适应症，在这些适应症中，缺氧会导致疾病病理，如持续性 新生儿肺高压16、17和新生儿窒息18-22。 Omniox，Inc.©2016机密-禁止分发