Effects of intramyocardial injection of phVEGF‐A<sub>165</sub> as sole therapy in patients with refractory coronary artery disease – 12‐month follow‐up: Angiogenic gene therapy

Sarkar, Nondita; Rück, Andreas; Källner, Göran; Y‐Hassan, Shams; Blomberg, Pontus; Islam, Khalid B.; Linden, Jan van der; Lindblom, Dan; Nygren, Åke; Lind, Britta; Brodin, Lars‐Åke; Drvota, Viktor; Sylvén, Christer

doi:10.1046/j.1365-2796.2001.00905.x

Cited by 65 publications

(42 citation statements)

References 16 publications

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“…In this sense, we corroborated with studies in humans [29] and animals [28,30], where have been documented a stabilization or improvement in ventricular function. In addition, experimental observations also indicate that VEGF exerts a direct effect on cardiomyocyte contractility after its interaction with VEGF receptor-1 and the consequent activation of PLCγ1 [28].…”

Section: Function and Maximal Oxygen Consumptionsupporting

confidence: 89%

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

Rodrigues¹,

Mostarda²,

Rosa³

2012

J Diabetes Metab

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Despite the increased amount of evidence about the benefits of human vascular endothelial growth factors by plasmid (pHuVEGF 165 ) based gene transfer after an ischemic event, the effects of pHuVEGF 165 therapy in diabetic hearts after myocardial infarction (MI) remains poorly investigated. We evaluated the effects of intramyocardial pHuVEGF 165 injection on left ventricular (LV) morphometry, function and blood flow, maximal oxygen consumption (VO 2 max), and the total mortality rate of diabetic rats after MI. Male Wistar rats were divided into control (C), myocardial infarction+saline injection (I+SAL), myocardial infarction+pHuVEGF 165 injection (I+VEGF), diabetes+myocardial infarction+saline injection (DI+SAL), and diabetes+myocardial infarction+pHuVEGF 165 injection (DI+VEGF). MI was induced after 15 days of streptozotocin diabetes induction. One day after MI, the animals received pHuVEGF 165 or saline intramyocardial injection. LV function and maximal oxygen consumption (VO 2 max) were evaluated at the initial injection and 30 days after injections. MI area evaluation showed an additional reduction in DI+VEGF (8±1%) in comparison with group I+VEGF (31±3%). Improvement in systolic function, evaluated invasively and noninvasively, lung wet/dry weight ratio, and VO 2 max were observed in both pHuVEGF 165 injected groups. Consequently, mortality rate was reduced in I+VEGF (19%) and DI+VEGF (12.5%) when compared with I+SAL (48%) and DI+SAL (37.5%) groups. In conclusion, pHuVEGF 165 therapy resulted in reduced MI area, stabilization and maintenance of left ventricular function, increased VO 2 max, and reduced mortality in MI animals, diabetic or not. These results highlight the importance of continuing experimental studies and controlled clinical trials of gene therapy for ischemic cardiomiopathy associated with the pathological conditions of diabetes.

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Section: Function and Maximal Oxygen Consumptionsupporting

confidence: 89%

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

Rodrigues¹,

Mostarda²,

Rosa³

2012

J Diabetes Metab

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“…20,21 The only reported, major side effect was the occurrence of a remarkable edema of the leg, probably due to the potent permeabilizing activity of VEGF. 22 A series of over 20 clinical trials followed in the late 1990s and early 2000s, entailing the injection of naked plasmid DNA encoding VEGF to the myocardium of patients with severe coronary artery disease (CAD) not amenable to surgical revascularization either through a mini left anterior thoracotomy [23][24][25][26][27][28] or by a transendocardial approach using a NOGA catheter. 29 Even more recently, an open-label, uncontrolled Phase I trial with a VEGF-A 165 plasmid (the GENESIS I trial) was carried out in Argentina by direct intramyocardial injection in 10 patients.…”

Section: Clinical Use Of Vegfmentioning

confidence: 99%

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

2012

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“…HGF, FGF, and NOS have also been investigated. The EUROINJECT trials, one of the biggest non-viral gene delivery clinical trials, delivered VEGF-A165 intramyocardially [115,117,128]. Perfusion appeared to be enhanced, anginal class improved, and exercise capacity extended [129].…”

Section: Figurementioning

confidence: 99%

Non‐viral gene therapy for myocardial engineering

Holladay

O’Brien

Pandit

2010

WIREs Nanomed Nanobiotechnol

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Despite significant advances in surgical and pharmacological techniques, myocardial infarction remains the main cause of morbidity in the developed world because no remedy has been found for the regeneration of infarcted myocardium. Once the blood supply to the area in question is interrupted, the inflammatory cascade, among other mechanisms, results in the damaged tissue becoming a scar. The goals of cardiac gene therapy are essentially to minimize damage, to promote regeneration or some combination thereof. While the vector is, in theory, less important than the gene being delivered, the choice of vector can have a significant impact. Viral therapies can have very high transfection efficiencies, but disadvantages include immunogenicity, retroviralmediated insertional mutagenesis and the expense and difficulty of manufacture. For these reasons, researchers have focused on non-viral gene therapy as an alternative. In this review, naked plasmid delivery, or the delivery of complexed plasmids, and cellmediated gene delivery to the myocardium will be reviewed. Pre-clinical and clinical trials in the cardiac tissue will form the core of the discussion. While unmodified stem cells are sometimes considered therapeutic vectors based on paracrine mechanisms of action basic understanding is limited. Thus, only genetically modified cells will be discussed as cell-mediated gene therapy.Ischemic heart disease, which includes acute damage due to myocardial infarction (MI) and chronic damage due to atherosclerotic narrowing of vessels, accounts for 35% of deaths reported in the United States every year [1]. MI, which is literally the death of cardiac tissue due to lack of 2 oxygen supply, is the result of the occlusion of a coronary artery. Within a few hours of interrupted blood supply, affected cardiomyocytes die. While the body has adaptive mechanisms, such as hypertrophy of the undamaged cardiac muscle and the development of collateral blood supply to minimize the damage, ischemic heart disease remains the most common cause of death in developed countries [2].The delivery of plasmid DNA to the myocardium is a complicated problem as the transfection efficiency of unmodified DNA is quite low, but complexation with agents designed to improve transfection can increase the cytotoxicity of the treatment [3]. Delivery of uncomplexed plasmid DNA is conceptually the simplest gene delivery technique, but these plasmids have extremely low transfection efficiencies in vitro and are not particularly effective in vivo. Compared to viral vectors, transgene expression is almost negligible and the expression time is also very limited [4]. However, there are significant advantages in using plasmids instead of viruses, such as ease of preparation (large and small scale), very low immunogenicity (as there are essentially no protein or membrane components in the plasmid), capacity for long term storage, ease of recombinant manipulation and much larger expression cassettes [4]. A variety of non-viral techniques are available to improve...

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Effects of intramyocardial injection of phVEGF‐A₁₆₅ as sole therapy in patients with refractory coronary artery disease – 12‐month follow‐up: Angiogenic gene therapy

Abstract: Abstract. Sarkar N, Ru È ck A, Ka Èllner G, Y-Hassan S, Blomberg P, Islam KB, van der Linden J, Lindblom D, Nygren AT, Lind B, Brodin L-A Ê , Drvota V, Sylve Ân C

Cited by 65 publications

References 16 publications

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

Non‐viral gene therapy for myocardial engineering

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Effects of intramyocardial injection of phVEGF‐A165 as sole therapy in patients with refractory coronary artery disease – 12‐month follow‐up: Angiogenic gene therapy

Abstract: Abstract. Sarkar N, Ru È ck A, Ka Èllner G, Y-Hassan S, Blomberg P, Islam KB, van der Linden J, Lindblom D, Nygren AT, Lind B, Brodin L-A Ê , Drvota V, Sylve Ân C

Cited by 65 publications

References 16 publications

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

Non‐viral gene therapy for myocardial engineering

Contact Info

Product

Resources

About

Effects of intramyocardial injection of phVEGF‐A₁₆₅ as sole therapy in patients with refractory coronary artery disease – 12‐month follow‐up: Angiogenic gene therapy