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

Ian Y. Chen, Olivier Gheysens, Zongjin Li, Julia A. Rasooly, Qian Wang, Ramasamy Paulmurugan, Jarrett Rosenberg, Martin Rodriguez-Porcel, Juergen K. Willmann, David S. Wang, Christopher H. Contag, Robert C. Robbins, Joseph C. Wu, Sanjiv S. Gambhir

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1α) 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-1α expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1α-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-1α gene (HIF-1α-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1α-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1α-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1α-dependent vascular endothelial growth factor expression (r 2=0.88). Intramyocardial delivery of pcTnT-HIF-1α-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1α-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-1α therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1α-VP2 therapy in preclinical models of myocardial ischemia.

Original languageEnglish (US)
Pages (from-to)279-288
Number of pages10
JournalHuman Gene Therapy Methods
Volume24
Issue number5
DOIs
StatePublished - Oct 1 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Applied Microbiology and Biotechnology
  • Genetics
  • Pharmacology
  • Genetics(clinical)

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