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Noninvasive imaging of hypoxia-inducible factor-1a gene therapy for myocardial ischemia.

Noninvasive imaging of hypoxia-inducible factor-1a gene therapy for myocardial ischemia. Human gene therapy methods Chen, I. Y., Gheysens, O., Li, Z., Rasooly, J. A., Wang, Q., Paulmurugan, R., Rosenberg, J., Rodriguez-Porcel, M., Willmann, J. K., Wang, D. S., Contag, C. H., Robbins, R. C., Wu, J. C., Gambhir, S. S. 2013; 24 (5): 279-288

Abstract

Abstract Hypoxia-inducible factor-1 alpha (HIF-1a) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1a expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1a-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1a gene (HIF-1a-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1a-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1a-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1a-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1a-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1a-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1a therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1a-VP2 therapy in preclinical models of myocardial ischemia.

View details for DOI 10.1089/hgtb.2013.028

View details for PubMedID 23937265