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

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)活性降低一起被认为是一种有害的机制，但1)这种PP1过度活性假说是否适用于心肌病(CM)的遗传模型，以及2)选择性抑制PP1是否可以影响心力衰竭的进展仍有待确定。我们研究了在UMX7.1地鼠心肌病进展过程中PP和PKA活性的时间进程，并研究了PP1的内源性特异性抑制物-2(I-2)对PP1的抑制作用。我们发现：1)在金黄地鼠心肌病中，Pp1活性升高先于严重的左心功能不全，但不伴随PKA活性受损；2)Pp1抑制有助于通过改变过度的β-肾上腺素能刺激来预防进行性左心功能不全，并可成为治疗遗传性心肌病和相关心力衰竭的潜在靶点。在体内，显性负性磷蛋白突变体的CARS ac基因转移也可以防止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钙调节基因进行遗传修饰可以减缓心力衰竭的进展，因此它可能在临床上适用。

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