Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial ‘delivery–efficacy’ mismatch

Radke, Peter W.; Heinl-Green, Amanda; Frass, Oliver M.; Griesenbach, Uta; Ferrari, Stefano; Geddes, Duncan M.; Alton, Eric W.F.W.

doi:10.1038/sj.gt.3302296

Cited by 14 publications

(7 citation statements)

References 22 publications

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“…The dosing we used was 5-10Â that was used in previous studies. 29,30 Furthermore, the injectate concentration and volume clearly modulate myocardial gene expression and need to be carefully accounted for in future trials. We also invoked an RU5 enhancer element to increase peak gene expression which significantly increased the biological effect observed in early rodent studies.…”

Section: Discussionmentioning

confidence: 99%

SDF-1 in myocardial repair

et al. 2012

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Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results. Gene Therapy (2012) 19, 583-587; doi:10.1038/gt.2012.32Keywords: acute myocordial infarction; regenerative medicine; stem cells; chemokines INTRODUCTIONOver a decade ago we hypothesized that stem cell-based repair of ischemic tissue is a natural response to tissue injury but that it is clinically inefficient because of the short-lived nature of the molecular signals regulating the process, not a lack of stem cells. At that time it was of great interest to us that stem cells in the blood stream homed to the myocardium in animal models of acute myocardial infarction (AMI), but not in models of chronic ischemic cardiomyopathy. These observations led us to investigate potential regulators of stem cell homing. We eventually identified stromal cell-derived factor-1 (SDF-1, aka CXCL12) as the key regulator of stem cell migration to sites of tissue injury. 1 More recently studies have extended the relevance of the SDF-1:CXCR4 axis by demonstrating its critical importance in cardiogenic specification during development. 2 As that initial observation we have demonstrated that transient engineered-cell-based 3 or plasmid-based 4 overexpression of SDF-1 in ischemic cardiomyopathy improved cardiac function. Furthermore, we have demonstrated that delivery of mesenchymal stem cells engineered to overexpress SDF-1 at the time of AMI leads to improvement in cardiac function. 5 Research by our laboratory and others have demonstrated that mechanism of action of SDF-1 overexpression in AMI and chronic heart failure (CHF) are clearly multifactorial including both systemic and direct trophic effects. [4][5][6] The initiation of endogenous stem cell-based repair appears blunted because of the natural short-term expression of SDF-1 at the time of AMI. 1 Furthermore, there appears to be commonalities associated with the mechanisms of action of SDF-1 in AMI and CHF as well as some distinct differences. We were the first to show that SDF-1 leads to the recruitment of cardiac st...

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Section: Discussionmentioning

confidence: 99%

SDF-1 in myocardial repair

et al. 2012

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“…Clinical trials using adenoviral delivery of VEGF121 in human patients with limb ischemia (72) indicate that local adenovirus injection is well tolerated and safe. Nonviral methods of angiogenic growth factor delivery have also been investigated, and delivery of a plasmid‐encoding VEGF165 was found to improve perfusion and myocardial function in a porcine chronic myocardial ischemia model (89). In another study, bolus injection of a plasmid‐encoding platelet‐derived growth factor did not significantly affect tissue formation, whereas sustained plasmid delivery from a polymer enhanced blood vessel formation (103).…”

Section: Delivery Of Angiogenic Factorsmentioning

confidence: 99%

Regeneration of vascularized bone

Hsiong

Mooney²

2006

Periodontology 2000

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“…7,29,30 However, because the molecular studies were performed at a single time point, 7 weeks after ameroid placement, it is likely that many of the acute changes in angiogenic mediators in response to chronic ischemia are not captured in this model. Additionally, morphometric assessment of new vessel formation by quantification of CD31 ϩ endothelial cells leads inevitably to the identification of all vessels, which may include newly formed, leaky, and unstable capillaries that may not be capable of improving myocardial perfusion.…”

Section: Limitationsmentioning

confidence: 99%

High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response

et al. 2006

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Background-Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine. Methods and Results-Yucatan pigs were fed either a normal (NORM group; nϭ7) or high-cholesterol diet, with (CHOL-ATR group; nϭ7) or without (CHOL group; nϭ6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery.

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Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial ‘delivery–efficacy’ mismatch

Cited by 14 publications

References 22 publications

SDF-1 in myocardial repair

SDF-1 in myocardial repair

Regeneration of vascularized bone

High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response

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