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Intracellular mitochondrial enzyme replacement therapy for heart and skeletalmyopathy in Barth Syndrome

细胞内线粒体酶替代疗法治疗巴特综合征的心脏和骨骼肌病

基本信息

批准号：
9546783
负责人：
MICHAEL T CHIN
金额：
$ 33.69万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9546783
关键词：
3-Methylglutaconic aciduria type 2 Acyltransferase Address Affect Animals Antibody Formation Apoptosis Biological Assay Blood Cardiolipins Cardiomyopathies Cells Clinical Cyclic Neutropenia Defect Disease Drug Kinetics Drug or chemical Tissue Distribution Echocardiography Electron Transport Endocytosis Engineering Enzyme-Linked Immunosorbent Assay Enzymes Functional disorder Generations Genes Genetic Diseases Half-Life Heart Heart failure Human Immature Granulocyte Immunofluorescence Immunologic Immunohistochemistry Impairment In Vitro Individual Injections Intracellular Transport Intravenous Laboratories Leukocytes Life Link Lysophospholipids Measures Mediating Metabolic Metabolism Mitochondria Morphology Mus Muscle Muscle Cells Muscle function Muscle hypotonia Mutation Myocardium Myography Myopathy Neutropenia Operative Surgical Procedures Pathogenesis Pathway interactions Patients Peptides Performance Permeability Phospholipids Physiologic pulse Plasma Population Production Property Proteins Reactive Oxygen Species Reagent Recombinants Respiration Role Sampling Serum Skeletal Muscle Tail Therapeutic Tissues Transacylase Veins constriction effective therapy enzyme deficiency enzyme replacement therapy experimental study immunogenicity improved in vivo liquid chromatography mass spectrometry middle age mouse model neutrophil novel pharmacokinetic characteristic respiratory skeletal treadmill uptake

项目摘要

Abstract: Intracellular mitochondrial enzyme replacement therapy for heart and skeletal myopathy in Barth Syndrome Barth Syndrome is an X-linked disorder resulting from defects in the gene encoding Tafazzin, an acyltransferase that modifies cardiolipin to the tetralinoleoyl form and is essential for mitochondrial respiration. The clinical manifestations of Barth Syndrome include muscular hypotonia, cardiomyopathy and neutropenia. At present, no effective therapy exists for affected individuals. The main issue that this project will address is whether an enzyme replacement strategy in which recombinant tafazzin is linked to a cellular penetrating peptide can promote uptake into tafazzin- deficient cells, restore cardiolipin remodeling, suppress abnormal production of mitochondrial reactive oxygen species (ROS), restore normal mitochondrial respiration, improve heart and skeletal muscle performance and improve neutropenia. This project will utilize a mouse model of Barth Syndrome from Jackson laboratories and initial studies to characterize baseline function in heart and skeletal muscle have been done. Other significant milestones include generation and purification of recombinant tafazzin protein that has been modified to contain a cellular permeability peptide, along with verification of its ability to enter cells and correct both cardiopin remodeling and mitochondrial respiration defects in vitro and in live animals. Other project findings are that tafazzin-deficient myocytes produce ROS at higher levels than control cells, and that exogenous tafazzin protein suppresses this excess ROS generation. In this proposal, elucidation of mechanisms by which recombinant tafazzin engineered for intracellular uptake can enter cells and correct the metabolic defects in tafazzin-deficient cells or animals will facilitate understanding of whether this novel recombinant tafazzin reagent can provide a treatment for cardiomyopathy, skeletal myopathy and neutropenia in Barth Syndrome patients.

翻译后摘要：细胞内线粒体酶替代疗法的心脏和骨骼 Barth综合征肌病巴斯综合征是一种X连锁疾病，由编码Tafazzin的基因缺陷引起，一种酰基转移酶，将心磷脂修饰为四氢萘油酰形式，是线粒体呼吸巴斯综合征的临床表现包括肌张力减退，心肌病和中性粒细胞减少症。目前，对受影响的个人没有有效的治疗方法。的该项目将解决的主要问题是，与细胞穿透肽连接的重组tafazzin可促进tafazzin的摄取。缺乏细胞，恢复心磷脂重塑，抑制线粒体反应性的异常产生，氧物种（ROS），恢复正常的线粒体呼吸，改善心脏和骨骼肌性能和改善中性粒细胞减少症。这个项目将利用巴斯综合征的小鼠模型来自杰克逊实验室和初步研究，以表征心脏和骨骼的基线功能肌肉已经完成了。其他重要的里程碑包括生成和纯化重组塔法津蛋白，已被修饰为含有细胞渗透性肽，沿着通过验证其进入细胞并纠正心肽重塑和线粒体的能力，体外和活体动物的呼吸缺陷。其他项目的发现是，肌细胞产生ROS的水平高于对照细胞，外源tafazzin蛋白抑制这种过量的ROS产生。在这项建议中，阐明了为细胞内摄取而设计的重组tafazzin可以进入细胞并纠正代谢紊乱，他法津缺陷细胞或动物的缺陷将有助于理解这种新的重组tafazzin试剂可提供心肌病、骨骼肌病和 Barth综合征患者的中性粒细胞减少症。