Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals

Dean, David A.

doi:10.1152/ajpcell.00613.2004

Cited by 61 publications

(50 citation statements)

References 133 publications

(181 reference statements)

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“…Perhaps the greatest advantage is that electroporation facilitates gene delivery to multiple cell layers, unlike gene delivery methods using liposomes, polymers, and viruses (14,15). In the case of the lung, electroporation of DNA administered to the airways causes DNA delivery and expression, not only in the airway and alveolar epithelium, but also in subepithelial cells, including fibroblasts, endothelial cells, and vascular and airway smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury

Mutlu

Machado-Aranda

Norton

et al. 2007

Am J Respir Crit Care Med

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Rationale: Acute lung injury and acute respiratory distress syndrome are common clinical syndromes resulting largely from the accumulation of and inability to clear pulmonary edema, due to injury to the alveolar epithelium. Gene therapy may represent an important alternative for the treatment and prevention of these diseases by restoring alveolar epithelial function. We have recently developed an electroporation strategy to transfer genes to the lungs of mice, with high efficiency and low inflammation. Objectives: We asked whether electroporation-mediated transfer of genes encoding subunits of the Na 1 ,K 1 -ATPase could protect from LPS-induced lung injury or be used to treat already injured lungs by up-regulating mechanisms of pulmonary edema clearance. Methods: Plasmids were delivered to the lungs of mice using transthoracic electroporation. Lung injury was induced by intratracheal administration of LPS (4 mg/kg body weight). Biochemical, cellular, and physiologic measurements were taken to assess gene transfer and lung injury. Measurements and Main Results: Improvements in wet-to-dry ratios, pulmonary effusions, bronchoalveolar lavage protein levels and cellularity, alveolar fluid clearance, and respiratory mechanics were seen after delivery of plasmids expressing Na 1 ,K 1 -ATPase subunits, but not control plasmids, in LPS-injured lungs. Delivery of plasmids expressing Na 1 ,K 1 -ATPase subunits both protected from subsequent lung injury and partially reversed existing lung injury by these measures.Conclusions: These results demonstrate that electroporation can be used effectively in healthy and injured lungs to facilitate gene delivery and expression. To our knowledge, this is the first successful use of gene delivery to treat existing lung injury, and may have future clinical potential.

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Section: Discussionmentioning

confidence: 99%

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury

Mutlu

Machado-Aranda

Norton

et al. 2007

Am J Respir Crit Care Med

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“…A T3-responsive Firefly luciferase vector (pLuc-TRE) and a normalization Renilla luciferase vector (pRen-C) were constructed and coinjected into the myocardium via thoracotomy to selectively transfect cardiomyocytes (24,25). Reporter activity was assayed in ventricular homogenates 5 days later.…”

Section: Figurementioning

confidence: 99%

Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats

Simonides¹,

Mulcahey²,

Redout³

et al. 2008

J. Clin. Invest.

161

176

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Thyroid hormone is a critical determinant of cellular metabolism and differentiation. Precise tissue-specific regulation of the active ligand 3,5,3′-triiodothyronine (T3) is achieved by the sequential removal of iodine groups from the thyroid hormone molecule, with type 3 deiodinase (D3) comprising the major inactivating pathway that terminates the action of T3 and prevents activation of the prohormone thyroxine. Using cells endogenously expressing D3, we found that hypoxia induced expression of the D3 gene DIO3 by a hypoxiainducible factor-dependent (HIF-dependent) pathway. D3 activity and mRNA were increased both by hypoxia and by hypoxia mimetics that increase HIF-1. Using ChIP, we found that HIF-1α interacted specifically with the DIO3 promoter, indicating that DIO3 may be a direct transcriptional target of HIF-1. Endogenous D3 activity decreased T3-dependent oxygen consumption in both neuronal and hepatocyte cell lines, suggesting that hypoxia-induced D3 may reduce metabolic rate in hypoxic tissues. Using a rat model of cardiac failure due to RV hypertrophy, we found that HIF-1α and D3 proteins were induced specifically in the hypertrophic myocardium of the RV, creating an anatomically specific reduction in local T3 content and action. These results suggest a mechanism of metabolic regulation during hypoxic-ischemic injury in which HIF-1 reduces local thyroid hormone signaling through induction of D3.

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“…14 Some recent review articles address the technical aspects of EP-enhanced non-viral gene therapy. 4,11,15 After in vivo gene electrotransfer into skeletal muscle, the duration of gene expression can range from several weeks to well over a year, depending on the construct and species. The more than 300 reported studies using direct intramuscular (i.m.)…”

Section: Introductionmentioning

confidence: 99%

Plasmid-based gene therapy of diabetes mellitus

Prud’homme

Draghia-Akli²,

Wang

2007

Gene Ther

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Type I diabetes mellitus (T1D) is due to a loss of immune tolerance to islet antigen and thus, there is intense interest in developing therapies that can re-establish it. Tolerance is maintained by complex mechanisms that include inhibitory molecules and several types of regulatory T cells (Tr). A major historical question is whether gene therapy can be employed to generate Tr cells. This review shows that gene transfer of immunoregulatory molecules can prevent T1D and other autoimmune diseases. In our studies, non-viral gene transfer is enhanced by in vivo electroporation (EP). This technique can be used to perform DNA vaccination against islet cell antigens and when combined with appropriate immune ligands results in the generation of Tr cells and protection against T1D. In vivo EP can also be applied for non-immune therapy of diabetes. It can be used to deliver protein drugs such as glucagon-like peptide 1 (GLP-1), leptin or transforming growth factor beta (TGF-b). These act in T1D or type II diabetes (T2D) by restoring glucose homeostasis, promoting islet cell survival and growth or improving wound healing and other complications. Furthermore, we show that in large animals EP can deliver peptide hormones, such as growth hormone releasing hormone (GHRH). We conclude that the non-viral gene therapy and EP represent a safe and efficacious approach with clinical potential.

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Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals

Cited by 61 publications

References 133 publications

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury

Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats

Plasmid-based gene therapy of diabetes mellitus

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Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals

Cited by 61 publications

References 133 publications

Electroporation-mediated Gene Transfer of the Na+,K+-ATPase Rescues Endotoxin-induced Lung Injury

Electroporation-mediated Gene Transfer of the Na+,K+-ATPase Rescues Endotoxin-induced Lung Injury

Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats

Plasmid-based gene therapy of diabetes mellitus

Contact Info

Product

Resources

About

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury

Electroporation-mediated Gene Transfer of the Na⁺,K⁺-ATPase Rescues Endotoxin-induced Lung Injury