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.

摘要：细胞内线粒体酶替代疗法治疗心脏和骨骼巴特综合征肌病巴斯综合症是一种 X 连锁疾病，由编码 Tafazzin 的基因缺陷引起，一种酰基转移酶，可将心磷脂修饰为四亚油酰基形式，对于线粒体至关重要呼吸。巴斯综合征的临床表现包括肌张力低下、心肌病和中性粒细胞减少症。目前，尚无针对受影响个体的有效治疗方法。这该项目将解决的主要问题是酶替代策略是否重组tafazzin与细胞穿透肽相连，可以促进tafazzin的吸收- 缺陷细胞，恢复心磷脂重塑，抑制线粒体反应性异常产生氧物质（ROS），恢复正常线粒体呼吸，改善心脏和骨骼肌性能并改善中性粒细胞减少症。该项目将利用巴斯综合症小鼠模型来自杰克逊实验室和初步研究，用于表征心脏和骨骼的基线功能肌肉已经做好了。其他重要的里程碑包括生成和纯化重组 tafazzin 蛋白已被修饰为含有细胞通透性肽，验证了其进入细胞并纠正心平素重塑和线粒体的能力体外和活体动物的呼吸缺陷。其他项目发现是缺乏tafazzin 肌细胞产生的 ROS 水平高于对照细胞，并且外源性 tafazzin 蛋白抑制这种过量的 ROS 生成。在该提案中，阐明了以下机制：用于细胞内摄取的重组 tafazzin 可以进入细胞并纠正代谢缺乏tafazzin的细胞或动物的缺陷将有助于了解这种新颖的重组tafazzin试剂可以治疗心肌病、骨骼肌病和巴特综合征患者中性粒细胞减少症。