Hoshijima Masahiko, Ikeda Yasuhiro, Iwanaga Yoshitaka, Minamisawa Susumu, Date Moto-o, Gu Yusu, Iwatate Mitsuo, Li Manxiang, Wang Lili, Wilson James M, Wang Yibin, Ross John, Chien Kenneth R
University of California, San Diego Institute of Molecular Medicine, La Jolla, California, USA.
Nat Med. 2002 Aug;8(8):864-71. doi: 10.1038/nm739. Epub 2002 Jul 22.
The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca(2+) uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28-30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.
基因治疗用于心肌病、心力衰竭及其他慢性心肌疾病的可行性目前尚未得到证实。在此，我们开发了一种体内重组腺相关病毒（rAAV）经冠状动脉递送系统，该系统可实现稳定、高效且相对具有心脏选择性的基因表达。我们使用rAAV在BIO14.6心肌病仓鼠中表达人受磷蛋白（PLN）的假磷酸化突变体，PLN是心脏肌浆网（SR）Ca（2+）循环的关键调节因子。rAAV/S16EPLN治疗增强了心肌SR Ca（2+）摄取，并在28 - 30周内抑制了左心室（LV）收缩功能和收缩性的进行性损害，从而保护心肌细胞免受细胞病变性细胞膜破坏。rAAV/S16EPLN治疗还在很大程度上预防了低LV收缩压和LV舒张功能恶化。因此，通过rAAV载体经冠状动脉进行S16EPLN基因转移是进行性扩张型心肌病及相关心力衰竭的一种潜在治疗方法。
