Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: Amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters

Abstract

The hereditary form comprises Ϸ1͞5 of patients with dilated cardiomyopathy (DCM) and is a major cause of advanced heart failure. Medical and socioeconomic settings require novel treatments other than cardiac transplantation. TO-2 strain hamsters with congenital DCM show similar clinical and genetic backgrounds to human cases that have defects in the ␦-sarcoglycan (␦-SG) gene. To examine the long-term in vivo supplement of normal ␦-SG gene driven by cytomegalovirus promoter, we analyzed the pathophysiologic effects of the transgene expression in TO-2 hearts by using recombinant adeno-associated virus vector. The transgene preserved sarcolemmal permeability detected in situ by mutual exclusivity between cardiomyocytes taking up intravenously administered Evans blue dye and expressing the ␦-SG transgene throughout life. The persistent amelioration of sarcolemmal integrity improved wall thickness and the calcification score postmortem. Furthermore, in vivo myocardial contractility and hemodynamics, measured by echocardiography and cardiac catheterization, respectively, were normalized, especially in the diastolic performance. Most importantly, the survival period of the TO-2 hamsters was prolonged after the ␦-SG gene transduction, and the animals remained active, exceeding the life expectancy of animals without transduction of the responsible gene. These results provide the first evidence that somatic gene therapy is promising for human DCM treatment, if the rAAV vector can be justified for clinical use.

Efficient and long-term intracardiac gene transfer in δ-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors

“…As a result the high percentage of therapeutic gene transfer in the cardiomyocytes, a recovery in physiological functions would almost be certain if the heart were in its in situ position. This notion is supported by two previous studies, where either a direct injection of left ventricle muscle with an AAV-d-sarcoglycan vector 30 or a coronary infusion with an Ad-d-sarcoglycan vector 2 have achieved significant physiological function recovery. The AAV vector treatment also slightly prolonged the lifespan of the cardiomyopathic TO-2 hamsters even though only a portion of the left ventricle received gene transfer by a single local injection of the d-sarcoglycan vector.…”

“…15 In addition, direct local injection of an AAV vector carrying d-sarcoglycan gene into the myocardium of Bio14.6 hamster has been recently reported. 30 However, AAV vector-mediated SG gene delivery through the coronary artery into the entire myocardium has not been reported.…”

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals

“…In this context, alternative approaches such as gene and cell therapy have attracted increased attention. Although transfer of pathophysiologically relevant genes has shown to be promising, [1][2][3][4] significant ongoing issues related to delivery, including vector efficiency, dose, specificity/tropism and safety are areas of concern. The use of adenoassociated virus (AAV) vectors to deliver genes to cardiomyocytes has been shown to be highly efficient both in vitro and in vivo.…”

“…The use of adenoassociated virus (AAV) vectors to deliver genes to cardiomyocytes has been shown to be highly efficient both in vitro and in vivo. [1][2][3] However, although there is continued development of AAV serotypes for improved cell/tissue-type targeting, 5 the issue remains of systemic delivery and safety. 6 As a consequence, delivery methods that result in homogeneous expression of the gene that are safe and well targeted need to be developed.…”

Augmentation of AAV-mediated cardiac gene transfer after systemic administration in adult rats

“…5,16 AAV serotype 2 vectors have been most intensively studied and have been successfully used in several experimental therapeutic approaches such as protection from ischemia/reperfusion injury in a rat model 17 or gene replacement therapy in cardiomyopathic hamsters 18,19 and revealed beneficial effects on neoangiogenesis, infarct size and cardiac function in a murine model of myocardial ischemia. 20 However, to achieve highly selective transduction of myocardial tissue, AAV vectors were administered by intramyocardial injection or selective perfusion of coronary arteries.…”