A Protein Biologic for the Treatment of Sepsis

用于治疗脓毒症的蛋白质生物制剂

• 批准号: 8000064
• 负责人: RAFAL M SMIGRODZKI
• 金额: $ 18.95万
• 依托单位: GENCIA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000064
• 关键词: Adverse effects; Animal Model; Antibiotics; Biogenesis; Cause of Death; Cell Death; Cessation of life; Complex; Consensus; Dose; Functional disorder; Glucocorticoids; Hepatocyte; Hour; Human; Hypoxia; Immunosuppression; Infection; Inflammation; Inflammatory Response; Ligation; Literature; Measures; Mitochondria; Modeling; Morbidity - disease rate; Mus; Organ; Organ failure; Output; Oxygen Consumption; Phase; Process; Production; Proteins; Puncture procedure; Recombinants; Running; Sepsis; Small Business Innovation Research Grant; Speed; Staging; Testing; Tissues; Work; aged; clinical application; improved; mitochondrial dysfunction; mortality; mtTF1 transcription factor; overexpression; public health relevance; research study; stressor; transcription factor

DESCRIPTION (provided by applicant): Sepsis and related multiple organ dysfunction are a major cause of mortality and morbidity, responsible for over 215 000 deaths per year in the US. Despite growing understanding of the pathomechanism of sepsis, treatment options are still limited primarily to antibiotics, glucocorticoids, and supportive measures. There is wide consensus that mitochondrial dysfunction, so called cytopathic hypoxia, develops over the course of sepsis, and becomes the defining feature of the late stage of the process. Cytopathic hypoxia is characterized by a reversible suppression of mitochondrial complex I, ATP production and oxygen consumption which result in immunosuppression and widespread organ failure. Experimental manipulations, such as overexpression of transcription factors that enhance mitochondrial biogenesis (e.g. the mitochondrial transcription factor A, TFAM), have been found effective in models of sepsis but clinical applications are hampered by lack of suitably powerful pharmacological biogenesis stimulators. Gencia developed a recombinant form of human TFAM (rhTFAM), modified to allow it to traverse cellular barriers and to be specifically imported into mitochondria. After being injected rhTFAM enters mitochondria in all tissues examined so far and acts as a transcription factor, rapidly (within hours) increasing complex I activity, oxygen consumption, mitochondrial mass and maximum ATP output by up to 150%, while decreasing ROS production. The magnitude, speed and persistence of mitochondrial biogenesis stimulation achieved with rhTFAM are larger than with any pharmacological agents described in the literature. Behaviorally, healthy mice treated with rhTFAM increased running endurance (rotarod latency) by 300%, and there were no significant side-effects over up to 10 months of dosing even in mice aged 34 months. Preliminary LPS sepsis animal model experiments show significantly improved survival in mice treated with rhTFAM. In this Phase I SBIR project we will test whether rhTFAM is capable of reversing of the cytopathic hypoxia observed in an LPS model of sepsis. Specific aims of the project are: 1) Determine if rhTFAM treatment ameliorates inflammation, mitochondrial function, and cell death in HepG2 and human primary liver cells challenged with LPS 2) Determine whether rhTFAM treatment alters mortality in c57/bl6 mice challenged with LPS. Confirmation of a beneficial effect of rhTFAM in LPS models of sepsis would pave the way for Phase II SBIR work where rhTFAM would be used in the CLP (cecal ligation and puncture) model of sepsis. PUBLIC HEALTH RELEVANCE: The aims carried out under this proposal will show feasibility for rhTFAM as a treatment for Sepsis. Sepsis is a systemic inflammatory response to infection and other severe stressors, and is the leading cause of death in the ICU setting, responsible for 215,000 fatalities per year in the US. Despite growing understanding of the pathomechanism of sepsis, treatment options are still limited primarily to antibiotics, glucocorticoids, and supportive measures.

描述（由申请人提供）：败血症和相关的多器官功能障碍是死亡率和发病率的主要原因，在美国每年造成超过215,000人死亡。尽管对脓毒症的病理机制了解越来越多，但治疗选择仍然主要局限于抗生素、糖皮质激素和支持措施。人们普遍认为，线粒体功能障碍，即所谓的细胞病变性缺氧，是在脓毒症的过程中发展起来的，并成为该过程晚期的决定性特征。细胞病变性缺氧的特点是线粒体复合体I、ATP产生和氧气消耗的可逆抑制，从而导致免疫抑制和广泛的器官衰竭。实验操作，如提高线粒体生物发生的转录因子的过表达（如线粒体转录因子A， TFAM），已被发现在脓毒症模型中有效，但临床应用受到缺乏适当的强大的药理生物发生刺激剂的阻碍。Gencia开发了一种重组形式的人类TFAM (rhTFAM)，经过修饰使其能够穿越细胞屏障并特异性地导入线粒体。注射后，rhTFAM进入到目前为止所检查的所有组织的线粒体，并作为转录因子，迅速（在数小时内）增加复合物I活性，氧气消耗，线粒体质量和最大ATP输出高达150%，同时减少ROS的产生。rhTFAM实现的线粒体生物发生刺激的幅度、速度和持久性比文献中描述的任何药理学药物都要大。行为上，用rhTFAM治疗的健康小鼠的跑步耐力（轮虫潜伏期）增加了300%，即使在34个月大的小鼠中，在长达10个月的剂量中也没有明显的副作用。初步LPS脓毒症动物模型实验显示，rhTFAM处理小鼠的存活率显著提高。在这个一期SBIR项目中，我们将测试rhTFAM是否能够逆转脓毒症LPS模型中观察到的细胞病变性缺氧。该项目的具体目标是：1)确定rhTFAM治疗是否改善HepG2和人原代肝细胞的炎症、线粒体功能和细胞死亡2)确定rhTFAM治疗是否改变LPS刺激的c57/bl6小鼠的死亡率。证实rhTFAM在LPS脓毒症模型中的有益作用将为II期SBIR研究铺平道路，其中rhTFAM将用于脓毒症的CLP（盲肠结扎和穿刺）模型。