Preclinical tests for gene therapy of advanced heart failure

晚期心力衰竭基因治疗的临床前试验

• 批准号: 14207033
• 负责人: TOYO-OKA Teruhiko
• 金额: $ 32.03万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207033/
• 关键词: Cardiac failure; Gene therapy; Pre-clinical studies; 細胞膜の透過性; ジストロフィン; 拡張型心筋症; サルゴグリカン; 細胞移植; rAAVベクター

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.

在前3个目标中，即（1）在大动物中制备拟人型晚期心力衰竭，（2）验证基因治疗的安全性和有效性，（3）开发基于重构细胞的治疗方法，取得了可观的结果。我们已经将先天性扩张型心肌病（DCM）的责任基因鉴定为δ-肌聚糖基因的突变（Sakamoto等人，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等，PNAS，2002）。与其他载体不同，rAAV具有安全性和生物学惰性。为了扩大我们的项目，利用猿类进行临床研究，我们花了一年半的时间获得文部科学省的许可。我们的最终范例是，心力衰竭是通过继发于肌营养不良蛋白破坏和肌膜通透性增加的共同机制进行的，而不管遗传或获得性起源以及急性或慢性过程对一般心力衰竭（包括人DCM）是常见的，这是非常宝贵的，因为这些数据不是在不使用猿的情况下从伦理上获得的（Toyo-oka et al.，PNAS，2004）。这些结果将为临床应用提供一个有前途的成果，并要求未来的资金。

项目成果

A novel scheme of dystrophin disruption for the progression of advanced heart failure (A review).

抗肌营养不良蛋白破坏治疗晚期心力衰竭进展的新方案（综述）。

• 发表时间: 2005
• 期刊: Biochim.Biophys.Acta (印刷中)
• 作者: Takahashi M. et al.;Kawada T. et al.;Kawada T. et al.
• 通讯作者: Kawada T. et al.

Hakamada-Taguchi R, Uehara Y, Haebara T, Negoro H, Toyo-oka T: "The relationship between changes in normal-range systolic blood pressure and cognitive function in middle-aged healthy women"Hypertens Res.. 25(4). 565-569 (2002)

Hakamada-Taguchi R、Uehara Y、Haebara T、Negoro H、Toyo-oka T：“中年健康女性收缩压正常范围变化与认知功能的关系”Hypertens Res.. 25(4)。

Shin WS, Hemmi C, Toyo-oka T: "Methods in Molecular Biology"Co-culture and crosstalk between endothelial cells and vascular smooth muscle cells mediated by intracellular calcium. Med.Res.Council. 347-357 (2002)

Shin WS、Hemmi C、Toyo-oka T：“分子生物学方法”细胞内钙介导的内皮细胞和血管平滑肌细胞之间的共培养和串扰。

A novel paradigm for the development of advanced heart failure-Assessment by gene therapy-.

晚期心力衰竭发展的新范例——基因治疗评估——。

• 发表时间: 2005
• 期刊: Pharmacol. & Therap. (In press)
• 作者: Kawada T;Masui F;Kumagai H;Koshimizu M;Nakazawa M;Toyo-oka T.
• 通讯作者: Toyo-oka T.

Hori K, Shin WS, Hemmi C, et al.: "High fidelity SNP genotyping using sequence-specific primer elongation and fluorescence correlation spectroscopy."Curr Pharm Biotechnol.. 4. 477-484 (2003)

Hori K、Shin WS、Hemmi C 等人：“使用序列特异性引物延伸和荧光相关光谱进行高保真 SNP 基因分型。”Curr Pharm Biotechnol.. 4. 477-484 (2003)