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

尽管蛋白磷酸酶（PP） 1活性的增加与蛋白激酶a （PKA）活性的损害在几种心力衰竭模型中被认为是一种有害的机制，但仍有待确定1)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是否会影响心力衰竭的进展。我们描述了UMX7.1仓鼠心肌病进展过程中PP和PKA活性的时间过程，并研究了抑制剂-2 （I-2）对PP1的抑制作用，抑制剂-2是一种内源性的PP1特异性抑制剂，如我们之前所述，使用体内高效心脏基因传递系统。我们发现1)在仓鼠心肌病中，PP1活性升高发生在严重的左室功能障碍之前，但不伴随PKA活性受损；2)PP1抑制有利于通过调节过度的β-肾上腺素能刺激来预防进行性左室功能障碍，并可能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，显性磷蛋白阴性突变体的基因转移也能阻止大鼠梗死后心力衰竭的进展。有数据表明，通过体细胞基因转移对Ca2+调节基因进行基因修饰可以缓解心力衰竭的进展，因此可能适用于临床环境

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