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被设计为 给缺氧组织充氧。由我们的第一阶段/第二阶段快速通道SBIR和 与我们的合作者、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)，OMX具有解决高度未满足的需求的潜力 保护心肌功能，降低新生儿体外循环手术的并发症。 这项SBIR IIB期提案的目标是推动OMX作为一种新的生物治疗药物的开发 体外循环对新生儿缺氧组织氧合的治疗作用 并保护心肌和外周器官功能。我们建议确认一种更稳定的变种 OMX保护CPB后心肌和外周器官功能及确定最佳给药方案 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 (良好制造规范)合同开发和制造组织(CDMO)，包括 过程和分析开发(目标3)，并准备并提交IND，用于在 新生儿(目标4)。在接受CPB的新生儿和儿童患者中，尚待良好的安全性和有效性数据， Omniox计划将OMX的使用扩大到其他儿科适应症，在这些适应症中，缺氧会导致疾病病理 例如新生儿持续的肺动脉高压16、17和新生儿窒息18-22。