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: 10761664
• 负责人: JEFFREY R FINEMAN
• 金额: $ 99.96万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761664
• 关键词: Acute; Address; Advanced Development; Animal Model; Aorta; Asphyxia Neonatorum; Award; Biological Response Modifier Therapy; Blood flow; Bypass; CHD1 gene; California; Cardiac Surgery procedures; Cardioplegic Solutions; Cardiopulmonary; Cardiopulmonary Bypass; Caring; Carrier Proteins; Carrying Capacities; Cerebrum; Child; Childhood; Clinical; Closure by clamp; Congenital Heart Defects; Contracts; Data; Defect; Development; Disease; Disease model; Dose; Endothelin; Environment; Exposure to; Formulation; Free Radicals; Functional disorder; Good Manufacturing Process; Heart; Heart Abnormalities; Hemorrhagic Shock; Hepatic; Human; Hypoxia; Induced Heart Arrest; Infant; Ischemia; Kidney; Kidney Failure; Lead; Left; Liver; Lung; Medical; Modeling; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Neonatal; Neurologic Deficit; Newborn Infant; Nitric Oxide; Operative Surgical Procedures; Organ; Organ Preservation; Oxygen; Pamphlets; Pathology; Patients; Performance; Perioperative; Peripheral; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase Ia/Ib Clinical Trial; Postoperative Complications; Postoperative Period; Process; Production; Proteins; Regimen; Research Personnel; Safety; San Francisco; Shunt Device; Small Business Innovation Research Grant; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; Universities; Variant; analytical method; antagonist; body system; cardiac repair; clinically relevant; congenital heart disorder; deprivation; design; experience; heart function; heart preservation; hemodynamics; hypoperfusion; hypoxic ischemic injury; improved; inhaled nitric oxide; lamb model; manufacturing organization; manufacturing process; neonatal patient; neonatal pulmonary hypertension; neonate; novel; organ injury; pediatric patients; preclinical study; preservation; protective effect; stem; therapeutic candidate; 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’s lead therapeutic candidate, OMX, is designed to oxygenate hypoxic tissues. Supported by preliminary data from our Phase I/II Fast-Track SBIR and generated with our collaborators, neonatal and pediatric care intensivists Drs. Fineman and Maltepe at the University of California, San Francisco (UCSF), OMX has the potential to address a high unmet need of preserving myocardial function and decreasing morbidity associated with neonatal CPB surgery. The objective of this SBIR Phase IIB proposal is to advance 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 confirm that a more stable variant of OMX preserves myocardial and peripheral organ function after CPB and identify the optimal dose regimen for OMX efficacy (Aims 1 and 2), adapt and optimize a scalable production process suitable for transfer to a GMP (Good Manufacturing Practice) contract development and manufacturing organization (CDMO), including process and analytical development (Aim 3), and prepare and submit an IND for a Phase 1 clinical trial in neonates (Aim 4). 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.

1.项目总结/摘要 Omniox正在开发一种独特的氧气输送蛋白OMX，作为保护心肌的治疗方法。 和外周器官功能，并显着降低新生儿心肺复苏后的发病率 在先天性心脏病（CHD）的外科手术矫正期间，在出生的约4万名儿童中， 每年约有10，000名冠心病患者需要紧急手术修复心脏缺陷1，2。高达60%的婴儿 接受CPB的患者将经历可能导致外周器官功能障碍的术后并发症， 长期神经功能缺损3 -15. 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，目前没有或有希望的治疗方法针对CPB手术期间的缺氧， 阻止或减轻其对下游的破坏性影响。Omniox的主要候选治疗药物OMX， 来修复缺氧组织。由我们的I/II期快速通道SBIR的初步数据支持， 与我们的合作者，新生儿和儿科护理重症监护医生Fineman博士和马尔泰佩在 加州大学旧金山分校弗朗西斯科（UCSF），OMX有潜力解决以下高度未满足的需求： 保护心肌功能和降低新生儿CPB手术相关的发病率。 SBIR第IIB阶段提案的目的是推进OMX作为一种新型生物制剂的开发， 通过证明其在氧合缺氧组织中的治疗效用来治疗接受CPB的新生儿 并保护心肌和外周器官功能。我们建议确认，一个更稳定的变体， OMX在CPB后保护心肌和外周器官功能，并确定最佳剂量方案， OMX功效（目标1和2），调整和优化适合转移到GMP的可扩展生产工艺 (Good制造实践）合同开发和制造组织（CDMO），包括 工艺和分析开发（目标3），并准备和提交IND用于1期临床试验 新生儿（目标4）。在接受CPB的新生儿和儿科患者中获得良好的安全性和有效性数据之前， Omniox计划将OMX的使用扩展到缺氧驱动疾病病理学的其他儿科适应症 例如在婴儿中持续性肺动脉高压16、17和出生窒息18 -22。