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

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。其他重要的里程碑包括生成和纯化 一种重组tafazzin蛋白，其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。

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.