Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector

Christopher J. Magovern, Charles A. Mack, John Zhang, Rebecca T. Hahn, Wilson Ko, O. Wayne Isom, Ronald Crystal, Todd K. Rosengart

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Background. Direct myocardial gene transfer is a modality that involves the introduction of genetic information into myocardial tissue to achieve a therapeutic effect. This study was designed to characterize the temporal and spatial limits of gene expression and to determine the safety of direct myocardial gene transfer in a large animal model using replication-deficient adenovirus vectors. Methods. Mongrel dogs underwent left thoracotomy and direct myocardial injections (100 μL/injection) of adenovirus vectors (109 pfu) carrying the DNA for the reporter enzyme chloramphenicol acetyl transferase or the angiogenic protein vascular endothelial growth factor. Two to 14 days after vector administration, regional protein expression was evaluated in myocardium and distant organs. Left ventricular function, assessed by echocardiography, and routine hematologic and biochemical indices were evaluated before and after vector administration. Results. Peak levels of chloramphenicol acetyl transferase activity were detected 2 days after vector administration, and levels above baseline persisted for at least 14 days. Local chloramphenicol acetyl transferase activity was detected at distances at least as far as 1.5 cm from the site of injection. Chloramphenicol acetyl transferase activity in distant organs was less than 0.1% of that in injected myocardium 7 days after vector administration. Localized expression of vascular endothelial growth factor was achieved for up to 7 days after a single vector administration. Cardiac function and laboratory values were unchanged during the study. Conclusions. Adenovirus-mediated direct myocardial gene transfer can be accomplished safely in a large animal model, providing high levels of protein expression in a greater spatial distribution than previously reported, with minimal transfection of distant organs. Sustained and localized expression of a potent angiogenic mediator has been accomplished, which may provide an innovative strategy to stimulate angiogenesis in ischemic myocardium.

Original languageEnglish
Pages (from-to)425-434
Number of pages10
JournalAnnals of Thoracic Surgery
Volume62
Issue number2
DOIs
Publication statusPublished - 1 Jan 1996
Externally publishedYes

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Chloramphenicol
Transferases
Adenoviridae
Canidae
Myocardium
Vascular Endothelial Growth Factor A
Genes
Injections
Animal Models
Angiogenic Proteins
Therapeutic Uses
Thoracotomy
Left Ventricular Function
Transfection
Echocardiography
Proteins
Dogs
Safety
Gene Expression
DNA

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Magovern, C. J., Mack, C. A., Zhang, J., Hahn, R. T., Ko, W., Isom, O. W., ... Rosengart, T. K. (1996). Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector. Annals of Thoracic Surgery, 62(2), 425-434. https://doi.org/10.1016/0003-4975(96)00328-1

Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector. / Magovern, Christopher J.; Mack, Charles A.; Zhang, John; Hahn, Rebecca T.; Ko, Wilson; Isom, O. Wayne; Crystal, Ronald; Rosengart, Todd K.

In: Annals of Thoracic Surgery, Vol. 62, No. 2, 01.01.1996, p. 425-434.

Research output: Contribution to journalArticle

Magovern, Christopher J. ; Mack, Charles A. ; Zhang, John ; Hahn, Rebecca T. ; Ko, Wilson ; Isom, O. Wayne ; Crystal, Ronald ; Rosengart, Todd K. / Direct in vivo gene transfer to canine myocardium using a replication-deficient adenovirus vector. In: Annals of Thoracic Surgery. 1996 ; Vol. 62, No. 2. pp. 425-434.
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abstract = "Background. Direct myocardial gene transfer is a modality that involves the introduction of genetic information into myocardial tissue to achieve a therapeutic effect. This study was designed to characterize the temporal and spatial limits of gene expression and to determine the safety of direct myocardial gene transfer in a large animal model using replication-deficient adenovirus vectors. Methods. Mongrel dogs underwent left thoracotomy and direct myocardial injections (100 μL/injection) of adenovirus vectors (109 pfu) carrying the DNA for the reporter enzyme chloramphenicol acetyl transferase or the angiogenic protein vascular endothelial growth factor. Two to 14 days after vector administration, regional protein expression was evaluated in myocardium and distant organs. Left ventricular function, assessed by echocardiography, and routine hematologic and biochemical indices were evaluated before and after vector administration. Results. Peak levels of chloramphenicol acetyl transferase activity were detected 2 days after vector administration, and levels above baseline persisted for at least 14 days. Local chloramphenicol acetyl transferase activity was detected at distances at least as far as 1.5 cm from the site of injection. Chloramphenicol acetyl transferase activity in distant organs was less than 0.1{\%} of that in injected myocardium 7 days after vector administration. Localized expression of vascular endothelial growth factor was achieved for up to 7 days after a single vector administration. Cardiac function and laboratory values were unchanged during the study. Conclusions. Adenovirus-mediated direct myocardial gene transfer can be accomplished safely in a large animal model, providing high levels of protein expression in a greater spatial distribution than previously reported, with minimal transfection of distant organs. Sustained and localized expression of a potent angiogenic mediator has been accomplished, which may provide an innovative strategy to stimulate angiogenesis in ischemic myocardium.",
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