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    ABSTRACT: The efficacy and safety of cardiac gene therapy depend critically on the level and the distribution of therapeutic gene expression following vector administration. We aimed to develop a titratable two-step transcriptional amplification (tTSTA) vector strategy, which allows modulation of transcriptionally targeted gene expression in the myocardium. We constructed a tTSTA plasmid vector (pcTnT-tTSTA-fluc), which uses the cardiac troponin T (cTnT) promoter to drive the expression of the recombinant transcriptional activator GAL4-mER(LBD)-VP2, whose ability to transactivate the downstream firefly luciferase reporter gene (fluc) depends on the binding of its mutant estrogen receptor (ERG521T) ligand binding domain (LBD) to an ER ligand such as raloxifene. Mice underwent either intramyocardial or hydrodynamic tail vein (HTV) injection of pcTnT-tTSTA-fluc, followed by differential modulation of fluc expression with varying doses of intraperitoneal raloxifene prior to bioluminescence imaging to assess the kinetics of myocardial or hepatic fluc expression. Intramyocardial injection of pcTnT-tTSTA-fluc followed by titration with intraperitoneal raloxifene led to up to tenfold induction of myocardial fluc expression. HTV injection of pcTnT-tTSTA-fluc led to negligible long-term hepatic fluc expression, regardless of the raloxifene dose given. The tTSTA vector strategy can effectively modulate transgene expression in a tissue-specific manner. Further refinement of this strategy should help maximize the benefit-to-risk ratio of cardiac gene therapy.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 08/2013; DOI:10.1007/s11307-013-0673-4 · 2.87 Impact Factor
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    ABSTRACT: Regenerative medicine has begun to define a new perspective of future clinical practice. The lack of basic data regarding to basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged tissue remains a major challenge for design stem cell therapies. So, visualization of injected stem cells provides additional insight into the future therapeutic benefits. Although current imaging modalities including magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, bioluminescence imaging, and fluorescence imaging offer some morphological as well as functional information, they lack the ability to assess and track in vivo biological phenomenon, a pivotal link for greater mechanistic understanding following cell-based intervention. This review will therefore discuss currently available in vivo imaging modalities and image processing techniques which may potentiate this field of research. - See more at: http://www.sciencedomain.org/abstract.php?iid=74&id=9&aid=279#.Ut7krxAo6Uk
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    ABSTRACT: Cell-based therapies are being developed for myocardial infarction (MI) and its consequences (e.g., heart failure) as well as refractory angina and critical limb ischemia. The promising results obtained in preclinical studies led to the translation of this strategy to clinical studies. To date, the initial results have been mixed: some studies showed benefit, whereas in others, no benefit was observed. There is a growing consensus among the scientific community that a better understanding of the fate of transplanted cells (e.g., cell homing and viability over time) will be critical for the long-term success of these strategies and that future studies should include an assessment of cell homing, engraftment, and fate as an integral part of the trial design. In this review, different imaging methods and technologies are discussed within the framework of the physiological answers that the imaging strategies can provide, with a special focus on the inherent regulatory issues.
    JACC. Cardiovascular imaging 05/2012; 5(5):559-65. DOI:10.1016/j.jcmg.2011.12.018 · 6.99 Impact Factor

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