Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs

Abstract

Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adenovirus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we established a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were randomly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.

Nonviral Gene Delivery to Mesenchymal Stem Cells Using Cationic Liposomes for Gene and Cell Therapy

“…In a few reports, some lipofection reagents were described to successfully introduce transgenes and small interfering RNAs (siRNAs) into MSC, while these cells have maintained their proliferation capacity and ability to differentiate into different mesodermal lineages (bone, cartilage and fat) without loss of transgene expression [ 12 ]. The main reason why cationic liposomes have demonstrated lower transfection efficiencies compared to viral vectors is that these nonviral vectors are not provided with specific devices for controlling intracellular gene trafficking, turning its optimization essential [ 13 , 14 ].…”

Catheter-Based Intramyocardial Delivery (NavX) of Adenovirus Achieves Safe and Accurate Gene Transfer in Pigs

“…Although the use of a mini-thoracotomy seems to be generally well tolerated, even in patients with advanced myocardial ischemia, nevertheless, the procedure has some risk associated with the administration of general anesthesia and some morbidity associated with surgical manipulation (particularly in patients with previous bypass surgery), and it limits the feasibility of repeat administrations [17]. Our previous animal studies have proven the efficiency of activating angiogenesis and improving cardiac function by direct intramyocardial delivery of HGF into the myocardium following open chest thoracotomy [18]. However, one pig died at week 3 after the second operation, while all the pigs in the present study survived till the end of the observation period.…”

Mechanistic, Technical, and Clinical Perspectives in Therapeutic Stimulation of Coronary Collateral Development by Angiogenic Growth Factors

“…46 The most widely used and characterized model is the ameroid constrictor model with normal resting myocardial perfusion but significant perfusion deficit during exertion or pharmacological stress. 46,50 The adaptive vascular response reaches its maximum within a few weeks after ameroid Translational TA studies in the pig ameroid constrictor model, using various angiogenic factors (VEGF, FGF, hepatocyte growth factor, angiopoietin-1, hypoxia-inducible factor-1 , neuropeptide Y), either as recombinant proteins or genes, have demonstrated significant therapeutic benefits assessed as improved regional myocardial perfusion and function, and in some studies increased angiogenesis and arteriogenesis 45,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66] (Table 1). This pig model was also used to evaluate other important features of TA, including therapeutic safety, dose-response relationships, and duration of therapeutic effects.…”