Novel Mitochondrial DNA Repair Enzyme for Heart Failure

治疗心力衰竭的新型线粒体 DNA 修复酶

• 批准号: 9408031
• 负责人: DAVID JOSEPH LEFER
• 金额: $ 29.65万
• 依托单位: EXSCIEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408031
• 关键词: Acute myocardial infarction; Address; Animals; Applications Grants; Attenuated; Base Excision Repairs; Biological Markers; Blood specimen; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Chimeric Proteins; Chronic; Clinic; Clinical; Clinical Trials; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Gene; Data; Development; Diagnosis; Dilatation - action; Disease Progression; Dose; EFRAC; Engineering; Family suidae; Foundations; Goals; Heart; Heart Diseases; Heart failure; Immunologics; Infarction; Injury; Left; Left Ventricular Function; Legal patent; Licensing; Medical; Metabolic; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Import Sequence; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial dysfunction; Myocardial tissue; Organ; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plant Roots; Play; Pre-Clinical Model; Preclinical Testing; Proteins; Reperfusion Therapy; Research; Role; Safety; Small Business Innovation Research Grant; Structure; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translations; Variant; Ventricular; animal efficacy; clinical application; clinically relevant; commercialization; coronary fibrosis; cytokine; efficacy testing; endonuclease III; experimental study; improved; in vivo; innovation; interest; mortality; mouse model; myocardial infarct sizing; novel; novel therapeutics; oxidant stress; preclinical development; preclinical efficacy; preclinical safety; pressure; prevent; programs; repaired; safety testing; tool; trafficking; uptake

ABSTRACT Previous studies have demonstrated that heart failure triggers and sustains increases in oxidative stress, inducing mitochondrial DNA (mtDNA) damage that then propagates myocardial injury resulting in cardiac dysfunction and myocardial cell death. Fortunately, mtDNA injury is reparable via endogenous base excision repair (BER) mechanisms. The rate-limiting step within BER is the amount of glycosylase present. Here we offer the novel therapeutic, Exscien1-III to catalyze and enhance mtDNA repair by trafficking to the mitochondria the glycosylase necessary to overcome this first and rate-determining stage, and thereby disrupt the propagation of myocardial disease. Exscien1-III is an innovatively engineered and patented, three-part fusion protein construct consisting of a TAT sequence (to facilitate cell uptake), a mitochondrial import sequence (to direct the therapeutic into the mitochondria) and a functional glycosylase (to help effect mtDNA repair). Exscien’s research variation of the protein also contains an HA tag for experimental immunological localization. Preliminary in vivo studies at LSU’s Cardiovascular Center of Excellence have demonstrated significant cardioprotective action using Exscien1-III in murine models of acute myocardial infarction (AMI) and heart failure (HF). The protein significantly attenuated myocardial infarct size and improved left ventricular function following myocardial ischemia and reperfusion in mice. Administration of Exscien1-III following the onset of severe HF attenuated myocardial fibrosis and left ventricular dilatation while improving left ventricular function in a murine pressure overload HF model. To further advance this fusion protein as an ameliorative therapeutic for HF, we seek to conduct a phased developmental program: Phase I - perform large animal efficacy, dosing and disposition testing of Exscien1-III; Phase II - utilize the results of Phase I to demonstrate efficacy of Exscien1-III, first as a therapy to prevent progression to HF following AMI and secondly, as a therapy to treat progressive HF in swine compromised with reduced ejection fraction. If successful, the evidence would form the foundation of an IND application to the FDA. Our commercialization objective is to develop the drug in-house as far as feasible (including planned early clinical trials), before ultimately out-licensing to a large pharmaceutical interest. With an estimated worldwide diagnosis of progressive heart failure in excess of 20 million, this therapy offers substantial commercial potential and has already attracted large “pharma” interest.

摘要 以前的研究表明，心力衰竭触发并维持氧化应激的增加， 应激，诱导线粒体DNA（mtDNA）损伤，然后传播心肌损伤 导致心脏功能障碍和心肌细胞死亡。幸运的是，mtDNA损伤是可以修复的。 通过内源性碱基切除修复（BER）机制。BER中的速率限制步骤是 存在糖基化酶的量。在这里，我们提供了新的治疗，Exscien 1-III催化 并通过向线粒体运输糖基化酶来增强线粒体DNA的修复， 克服这个第一和速率决定阶段，从而破坏心肌细胞的传播， 疾病Exscien 1-III是一种创新设计和专利的三部分融合蛋白 由达特序列（以促进细胞摄取）、线粒体输入序列（以促进细胞摄取）、线粒体输入序列（以促进细胞摄取）和线粒体输入序列组成的构建体。 (to将治疗剂直接导入线粒体）和功能性糖基化酶（以帮助影响线粒体DNA 修复）。Exscien的蛋白质研究变体还包含一个HA标签，用于实验性 免疫定位 路易斯安那州立大学心血管卓越中心的初步体内研究表明， Exscien 1-III在急性心肌梗死小鼠模型中的显著心脏保护作用 心肌梗死（AMI）和心力衰竭（HF）。该蛋白显著减小心肌梗死范围 改善小鼠心肌缺血再灌注后左心室功能。 在严重HF发作后给予Exscien 1-III可减轻心肌纤维化， 压力超负荷性心力衰竭小鼠左室扩张同时改善左室功能 模型为了进一步发展这种融合蛋白作为HF的改善治疗，我们寻求 进行阶段性开发计划：I期-进行大型动物有效性、给药和 Exscien 1-III的处置测试; II期-利用I期的结果证明疗效 Exscien 1-III，首先作为预防AMI后进展为HF的治疗，其次作为 在射血分数降低的猪中治疗进行性HF的方法。 如果成功，这些证据将成为向FDA提交IND申请的基础。我们 商业化目标是尽可能在内部开发药物（包括计划的 早期的临床试验），然后最终将许可证发放给大型制药公司。与 估计全世界诊断的进行性心力衰竭超过2000万，这种疗法 提供了巨大的商业潜力，并已经吸引了大量“制药”兴趣。