Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors

Raake, Philip; Hinkel, Rabea; Müller, Sebastian; Delker, Sebastian; Kreuzpointner, Robert; Kupatt, Christian; Katus, Hugo A.; Kleinschmidt, J A; Boekstegers, Peter; Müller, Oliver

doi:10.1038/sj.gt.3303035

Cited by 79 publications

(61 citation statements)

References 44 publications

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“…23 This method requires occlusion of the coronary vasculature for 3 min, allowing the vector of interest to dwell, resulting in improved protein expression. Another method requiring occlusion of the left anterior descending coronary artery (LAD) has been recently tested by Raake et al 24 Selective pressureregulated retro-infusion was used to deliver AAV vectors with success following a 20 min non-continuous retroinfusion into the anterior inter-ventricular vein. In comparison to these two methods, V-Focus infusion is constant and does not require coronary vasculature occlusion.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca 2+ ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 Â 10 10 d.r.p.; medium 1 Â 10 12 d.r.p. and high 1 Â 10 13 d.r.p.) in conjunction with an intra-coronary delivery group (2.5 Â 10 13 d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t max ; low dose À220 ± 70, P40.05; medium dose 125 ± 53, Po0.05; high dose 287 ± 104, Po0.05) and echocardiographically (fractional shortening: low dose À3 ± 2, P40.05; medium dose 1 ± 2, P40.05; high dose 6.5 ± 3.9, Po0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…However, antegrade delivery was slightly more effective in reducing miR-92a expression in the remote zone ( Figure 1B). Of note, local cardiac delivery of viral vectors such as adenoviruses 19 and adeno-associated viruses 20 was more effective with the retrograde approach. However, inhibition of miR-92 by LNA-92a by antegrade intracoronary infusion appears functionally equipotent to the retrograde delivery approach, most likely because of a higher capability of the smaller molecules to transit across target cell walls.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MicroRNA-92a Protects Against Ischemia/Reperfusion Injury in a Large-Animal Model

et al. 2013

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Background— MicroRNAs (miRs) are small noncoding RNAs that posttranscriptionally control gene expression. Small-animal studies suggest that miRs might offer novel therapeutic targets in cardiovascular diseases such as cardioprotection of murine hearts after myocardial infarction via miR-92a inhibitors. Because the functional benefits of miR-92a inhibitors in larger preclinical models are not known, we assessed the therapeutic efficacy of miR-92a inhibition in a porcine model of ischemia and reperfusion. Methods and Results— Pigs (n=5 per group) underwent percutaneous ischemia/reperfusion (60 min/72 h or 7 days, respectively). Locked nucleic acid–modified antisense miR-92a (LNA-92a) was applied either regionally (antegrade or retrograde) with a catheter or systemically (intravenously). LNA-92a significantly ( P <0.01) reduced miR-92a expression in the infarct zone regardless of the application venue. However, catheter-based delivery, but not intravenous infusion, of LNA-92a significantly ( P <0.05) reduced the infarct size compared with control LNA–treated pigs, which correlated with an improved ejection fraction and left ventricular end-diastolic pressure ( P <0.05). Histochemistry revealed that LNA-92a increased capillary density but decreased leukocyte influx and cardiac cell death. Complete loss of miR-92a in mice attenuated the infarct-related myocardial dysfunction to a larger extent than cardiomyocyte-specific miR-92a deletion. In vitro, LNA-92a protected against hypoxia/reoxygenation–induced cardiomyocyte cell death. Conclusions— Regional LNA-92a delivery reduces miR-92a levels and infarct size and postischemic loss of function. LNA-92a exerts cell-protective, proangiogenic, and anti-inflammatory effects. miR-92a inhibition might be a novel therapeutic tool to preserve cardiac function after ischemia.

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“…[9][10][11][12][13][14][15] However, these techniques have inherent risks that may outweigh their benefit. Therefore, the development of noninvasive but highly organ-specific systemic gene transfer approaches has been a major focus.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors

Cited by 79 publications

References 44 publications

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

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

Inhibition of MicroRNA-92a Protects Against Ischemia/Reperfusion Injury in a Large-Animal Model

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

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