Effects of novel adeno-associated virus-mediated muscle-directed gene transfer therapy in Fabry mouse : especially regarding cardiovascular systems

法布里病是一种以病理性细胞内鞘糖脂沉积为特征的遗传性溶酶体贮积症。这种疾病是由溶酶体α-半乳糖苷酶a的缺陷引起的，该基因位于X染色体区域xq22。Globotriaosylceramide （Gb3）在全身多器官易损细胞中逐渐积累，包括心血管、肾脏和脑血管系统。近年来，新的治疗策略不断涌现，包括临床引入的酶输注替代疗法和实验开发的基因转移疗法。我们开发了一种新的aav介导的Fabry小鼠肌肉定向基因转移疗法，该疗法对α-半乳糖A的长期全身递送（正常小鼠酶活性的25%）非常有效，从而完全清除多器官Gb3积累。在心血管系统方面，超声心动图和免疫组化检查显示，在结构和功能上抑制了心肌肥厚的发生。然而，在Fabry小鼠模型中，几乎没有检测到在临床条件下在病理生理中发挥重要作用的Gb3的积累，这可能是本实验研究的局限性之一。对缺血性心脏病或心力衰竭的发病机制和后果的理解的进展刺激了新型生物标志物的发展，并扩大了它们在不同潜在病理生理学光谱中的作用。我们构建了多生物标志物策略；包括1)心肌坏死（肌原纤维坏死膜损伤；H-FABP和肌钙蛋白T）， 2)冠状动脉斑块不稳定，3)心肌应激（舒张末期心室壁应激；BNP和NT-proBNP）的生物标志物。这些策略将有助于Fabry病的早期发现和治疗评估。为了未来的诊断和治疗评估，我们建立了心肌病模型，使用阿霉素心脏毒性作为替代，并评估了超声心动图和生物标志物的效用。作为本系列研究的总结，我们对Fabry病的心血管和肾脏表现、新的诊断方法以及新的治疗策略进行了综述，包括临床引入的酶输注替代疗法和实验开发的基因转移疗法。少

Fabry disease is an inherited lysosomal storage disorder characterized by a pathological intracellular glycosphingolipid deposition. The disease is caused by a deficit in the lysosomal enzyme α-galatosidase A, the gene for which is located in the X chrosomal region Xq 22. Globotriaosylceramide (Gb3) accumulate progressively in multi-organ vulnerable cells throughout the body, including cardiovascular, renal, and cerebrovascular systems. Novel therapeutic strategies for this disease have been developing in recent years, which include the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy.1.We have developed novel AAV-mediated muscle-directed gene transfer therapy for Fabry mouse which is very effective for long-term systemic delivery of α-gal A (25% of normal mice enzyme activity), resulting in complete clearance of multi-organs Gb3 accumulation.2.Regarding the cardiovascular system, echocardiographic and immunohistochemical exa … More minations demonstrated structural and functional suppression of the development of cardiac hypertrophy. However in the Fabry mouse mode, accumulation of Gb3 which should play an important role in the pathophysiology in clinical condition role was hardly detected, that might be one of limitation in this experimental study.3.Advances in the understanding of the pathogenesis and consequences of ischemic heart disease or heart failure have stimulated development of novel biomarkers, and expanded their role in the different spectrum of the underlying pathophysiology. We have constructed multi-biomarker strategy ; consisted of biomarkers for 1)myocardial necrosis (membrane damage to myofibril necrosis ; H-FABP and troponin T), 2)coronary plaque destabilization, 3)myocardial stress (end-diastolic ventricular wall stress ; BNP and NT-proBNP). These strategies would be clinically useful for the early detection and therapeutic assessment in the Fabry disease managements.4.For the future diagnostic and therapeutic assessments, we have developed cardiomyopathy model using adriamycin cardiotoxicity as the substitute, and assessed echocardiographic and biomarkers utilities.As the summary of the present study series, we have written a review on cardiovascular and renal manifestations of Fabry disease and the new diagnostic procedures, and the novel therapeutic strategies including the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy. Less