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. 项目概要/摘要 Omniox 正在开发一种独特的氧输送蛋白 OMX，作为保护心肌的治疗方法 和周围器官功能，并显着降低新生儿心肺术后的发病率 先天性心脏病 (CHD) 手术矫正期间的搭桥术 (CPB)。在大约 40,000 名出生的孩子中 每年约有 10,000 名患有先心病的婴儿需要紧急手术来修复心脏缺陷1, 2。高达 60% 的婴儿 接受体外循环（CPB）会出现术后并发症，可能导致周围器官功能障碍和 长期神经功能缺损3-15。 心肌和周围器官组织损伤的一个关键驱动因素是缺氧或缺氧3-15。 然而，目前尚无针对 CPB 手术期间缺氧的治疗方法或有希望的治疗方法。 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 被设计 恢复缺氧组织的生理氧水平。因此，OMX 有潜力解决高 保留心肌功能和改善与新生儿 CPB 手术相关的发病率的需求尚未得到满足。 与我们的合作者、新生儿和儿科重症监护医生一起。法恩曼和马尔特佩在 加州大学旧金山分校 (UCSF)，我们已经证明 OMX 可以减轻缺氧- 引起羔羊心肌功能障碍。此外，我们的初步数据表明 OMX： 1) 特别是在缺氧组织中恢复生理氧水平； 2）防止脑缺血后缺氧引起的细胞死亡； 3）在多个物种中稳定、安全且耐受性良好；和 4) 不增加自由基的产生或清除一氧化氮。 该快速通道 SBIR I/II 期提案的目标是完成 OMX 作为一种药物的临床前开发。 通过证明其治疗效用，用于治疗接受体外循环的新生儿的新型生物制剂 为缺氧组织供氧，保护心肌和周围器官功能。我们建议 1) 证明 OMX 在完整新生儿 CPB 期间和之后保留心肌和外周器官功能 羔羊（第一阶段），然后 2) 在临床相关的新生儿羔羊 CHD 模型中证明 OMX 的功效 正在进行 CPB（第二阶段）。这些数据将为新生儿和儿科临床试验的 IND 申请提供信息。 在接受 CPB 的新生儿和儿童患者获得良好的安全性和有效性数据之前，Omniox 计划 将 OMX 的使用范围扩大到缺氧导致疾病病理的其他儿科适应症，例如持续性缺氧 新生儿肺动脉高压16、17 和出生窒息18-22。 Omniox, Inc. ©2016 机密 – 不得分发