Development of gene therapy for treatment of dilated cardiomyopathy and associated heart failure

开发治疗扩张型心肌病和相关心力衰竭的基因疗法

• 批准号: 14370228
• 负责人: MATSUZAKI Masunori
• 金额: $ 9.41万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370228/
• 关键词: chronic hears failure; dilated cardiomyopathy; protein phosphatase 1; Adenovirus vector; Aden associated virus vector; cardiomyopathic hamster; High efficiency in vivo cardiac gene transfer; 遺伝子導入

Although increase in protein phosphatase (PP) 1 activity is proposed as a detrimental mechanism together with impairment of protein kinase A (PKA) activity in several models of heart failure, it remains to be determined 1) whether this PP1 over-activity hypothesis is applicable in genetic models of cardiomyopathy (CM) and 2) if selective inhibition of PP1 can affect heart failure progression. We characterized time course of PP and PKA activity in progression of UMX7.1 hamster cardiomyopathy and investigated the effect of PP1 inhibition by inhibitor -2 (I-2), an endogenous specific inhibitor of PP1 using in vivo high efficiency cardiac gene delivery system as we previously described. We found that 1) increase in PP1 activity precedes severe LV dysfunction but does not accompany impaired PKA activity in the hamster cardiomyopathy and 2) PP1 inhibition is beneficial for preventing progressive LV dysfunction by modifying excessive β-adrenergic stimulation and can be a potential target for treatment of genetic cardiomyopathy and associated heart failure. In vivo cards ac gene transfer of dominant negative phospholamban mutant also prevented progression of post infarction heart failure in rat. There data suggest that genetic modification of Ca2+ regulatory gene by somatic gene transfer alleviate progression of heart fail ure, thus it may be applicable in the clinical settings

尽管在几种心力衰竭模型中，蛋白磷酸酶（PP）1活性增加与蛋白激酶A（PKA）活性受损一起被认为是一种有害机制，但仍有待确定1）这种PP 1过度活性假说是否适用于心肌病（CM）的遗传模型和2）选择性抑制PP 1是否可以影响心力衰竭进展。我们表征了UMX7.1仓鼠心肌病进展中PP和PKA活性的时间过程，并研究了抑制剂-2（I-2）对PP 1抑制的影响，抑制剂-2（I-2）是PP 1的内源性特异性抑制剂，使用体内高效心脏基因递送系统，如前所述。我们发现：1）在仓鼠心肌病中，PP 1活性增加先于严重LV功能障碍，但不伴有PKA活性受损; 2）PP 1抑制通过改变过度的β-肾上腺素能刺激有利于预防进行性LV功能障碍，并可成为治疗遗传性心肌病和相关心力衰竭的潜在靶点。体内转基因显性负性受磷蛋白突变体cards ac也可预防大鼠梗死后心力衰竭的进展。这些数据表明，通过体细胞基因转移对Ca 2+调节基因进行遗传修饰可以减轻心力衰竭的进展，因此可能适用于临床环境

项目成果

Nakamura Hiroshi: "Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction : new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary

Nakamura Hiroshi：“供体心脏心肌梗塞后受体心脏左心室重塑和功能障碍的诱导：从新型异位移植冠状动脉中对肿瘤坏死因子-α的病理作用的新见解

Hoshijima Masahiko: "Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery"Nature Medicine. 8. 864-871 (2002)

Hoshijima Masahiko：“受磷蛋白的假磷酸化突变体通过体内心脏 rAAV 基因传递慢性抑制心力衰竭进展”《自然医学》。

Iwanaga Y, Hoshijima Y, Gu Y, Iwatate M, Dieterle T, Ikeda Y, Date M, Chrast J, Mat suzaki M, Peterson KL, Chien KR, Ross JJr: "Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats"

Iwanaga Y、Hoshijima Y、Gu Y、Iwatate M、Dieterle T、Ikeda Y、Date M、Chrast J、Mat suzaki M、Peterson KL、Chien KR、Ross JJr：“慢性受磷蛋白班抑制可预防进行性心脏功能障碍和梗死后的病理重塑

Hoshijima M et al.: "Chronic suppression of heart-failure progression by a pseudopho sphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery."Nature Medicine. 8. 864-871 (2002)

Hoshijima M 等人：“通过体内心脏 rAAV 基因传递，磷蛋白班的假磷磷酸化突变体对心力衰竭进展进行慢性抑制。”《自然医学》。

Okuda S et al.: "Valsartan restores sarcoplasmic reticulum function with no appreciable effect on resting cardiac function in pacing-induced heart failure."Circulation. 109. 911-919 (2004)

Okuda S 等人：“缬沙坦可恢复肌浆网功能，但对起搏引起的心力衰竭的静息心脏功能没有明显影响。”循环。