Preclinical tests for gene therapy of advanced heart failure

前3个目标取得了可观的成果，即：(1)大型动物模拟人类型晚期心力衰竭的制备；(2)基因治疗的安全性和有效性验证；(3)重建细胞治疗的发展。我们已经确定先天性扩张型心肌病（DCM）的致病基因是δ-肌聚糖基因的突变（Sakamoto et al.， PNAS,1997）。然后，我们首次成功地使用稳定和持久的rAAV载体进行基因治疗（Kawada et al， PNAS,2002）。与其他载体不同，rAAV具有安全性和生物惰性。为了延长我们的猿类临床研究项目，我们需要花费一年半的时间来获得教育、文化、科学技术部的许可。我们的最后一个范例是，心力衰竭是由一种继发于肌营养不良蛋白破坏和肌层渗透性增加的共同机制进行的，与遗传或获得性起源无关，急性或慢性过程是心力衰竭的共同特征，包括人类DCM，这是非常宝贵的，因为这些数据在没有使用类人猿的情况下是不符合伦理的（Toyo-oka等人，PNAS,2004）。这些结果将为临床应用提供一个有前途的成果，我们希望得到未来的资金支持。

Considerable results was obtained in the first 3 objects, i.e. (1)Preparation of advanced heart failure of human-mimicking type in large animals, (2)Verification of safety and efficacy of gene therapy and (3)Development of reconstructed cell-based therapy. We have identified responsible gene for congenital dilated cardiomyopathy (DCM) as a mutation of δ-sarcoglycan gene (Sakamoto et al., PNAS,1997). Then, we have for the first time succeeded in gene therapy with using stable and long-lasting rAAV vector (Kawada et al, PNAS,2002). Different from other vectors, rAAV was safe and biologically inert. To extend our project for clinical study using apes, we had to consume one and a half year for the permission of the Ministry of Education, Culture, Science and Technology. Our final paradigm that heart failure is proceeded by a common mechanism secondary to dystrophin disruption and increment of sarcolemmal permeability, irrespective of hereditary or acquired origins and acute or chronic processes was common to heart failure in general including human DCM was extremely precious, because these data were not ethically obtained without employing apes (Toyo-oka et al., PNAS,2004). These results would provide a promising fruit to develop for the clinical application, and we do ask future fund.