Electroporation-Mediated Gene Delivery of Na+,K+-ATPase, and ENaC Subunits to the Lung Attenuates Acute Respiratory Distress Syndrome in a Two-Hit Porcine Model

Emr, Bryanna; Roy, Somnath C.; Kollisch-Singule, Michaela; Gatto, Louis A.; Barravecchia, Michael; Lin, Xin; Young, Jennifer L.; Wang, Guirong; Liu, Jiao; Satalin, Joshua; Snyder, Kathy; Nieman, Gary F.; Dean, David A.

doi:10.1097/shk.0000000000000228

Cited by 26 publications

(35 citation statements)

References 35 publications

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“…51 This strategy appears to be a safe means of transferring genetic material to healthy lungs, and may be efficacious even in setting of acute and severe lung disease. 52, 53 …”

Section: Discussionmentioning

confidence: 99%

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Khoshnejad¹,

Shuvaev²,

Pulsipher³

et al. 2016

Bioconjugate Chem.

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Targeting nanocarriers to the endothelium, using affinity ligands to cell adhesion molecules such as ICAM-1 and PECAM-1, holds promise to improve the pharmacotherapy of many disease conditions. This approach capitalizes on the observation that antibody-targeted carriers of 100 nm and above accumulate in the pulmonary vasculature more effectively than free antibodies. Targeting of prospective nanocarriers in the 10–50 nm range, however, has not been studied. To address this intriguing issue, we conjugated monoclonal antibodies (Ab) to ICAM-1 and PECAM-1 or their single chain antigen-binding fragments (scFv) to ferritin nanoparticles (FNPs, size 12 nm), thereby producing Ab/FNPs and scFv/FNPs. Targeted FNPs retained their typical symmetric core-shell structure with sizes of 20–25 nm and ~4–5 Ab (or ~7–9 scFv) per particle. Ab/FNPs and scFv/FNPs, but not control IgG/FNPs, bound specifically to cells expressing target molecules and accumulated in the lungs after intravenous injection, with pulmonary targeting an order of magnitude higher than free Ab. Most intriguing, the targeting of Ab/FNPs to ICAM-1, but not PECAM-1, surpassed that of larger Ab/carriers targeted by the same ligand. These results indicate that: i) FNPs may provide a platform for targeting endothelial adhesion molecules with carriers in the 20 nm size range, which has not been previously reported; and, ii) ICAM-1 and PECAM-1 (known to localize in different domains of endothelial plasmalemma) differ in their accessibility to circulating objects of this size, common for blood components and nanocarriers.

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“…51 This strategy appears to be a safe means of transferring genetic material to healthy lungs, and may be efficacious even in setting of acute and severe lung disease. 52, 53 …”

Section: Discussionmentioning

confidence: 99%

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Khoshnejad¹,

Shuvaev²,

Pulsipher³

et al. 2016

Bioconjugate Chem.

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“…A second advantage is that its activity is only limited to the area of electrical field, thus avoiding potential systemic effects derived from vector dissemination. Studies from the laboratory of David Dean have demonstrated the applicability of this method of gene delivery in large animal models such as swine (37). The amount of energy used has been calculated in 0.2 joules/kg, much less than defibrillators in hospital practice (38).…”

Section: Discussionmentioning

confidence: 99%

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

et al. 2016

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Injured patients with lung contusion (LC) are at risk of developing bacterial pneumonia (PNA) followed by sepsis and death. A recent Genome-wide Association Study, showed FER gene expression positively correlating with survival rates among individuals with above conditions. We sought to determine if electroporation-mediated (EP) delivery of FER gene could indeed improve survival, in a lethal model of combined LC and PNA. C57BL/6 mice sustained unilateral LC, which preceded a 500 Klebsiella CFU inoculation by 6 hrs. In-between these insults, human FER plasmid (pFER) was introduced into the lungs followed by eight EP pulses applied externally (10ms at 200V/cm). Control groups included EP of empty vector (pcDNA3) or Na+/K+-ATPase genes (pPump) and no treatment (LC + PNA). We recorded survival, histology, lung mechanics, bronchial alveolar fluid (BAL), FER and inflammatory gene expression and bacteriology. The data shows that 7-day survival was significantly improved by pFER compared to control groups. pFER increased BAL monocytes and activated antibacterial response genes (NOS, Fizz). pFER treatment showed decreased lung and blood Klebsiella counts reaching, in some cases, complete sterilization. In conclusion, FER gene delivery promoted survival in LC+PNA mice via recruitment of activated immune cells, improving efficiency of bacterial clearance within contused lung

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“…While these plate electrodes are rather small using electrode surface areas of less than 1 cm 2 , larger plate electrodes can also be used safely for electroporation of larger organs or animals. For example, we have used defibrillation paddles and defibrillation electrode pads (10 × 15 cm) to deliver fields across the chests of 40-kg pigs for efficient gene delivery into the lungs (Dean, Barravecchia, Danziger, & Lin, 2011; Emr et al, in press). …”

Section: Electrodesmentioning

confidence: 99%

Electroporation-Mediated Gene Delivery

Young

Dean

2015

Advances in Genetics

Self Cite

129

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Electroporation has been used extensively to transfer DNA to bacteria, yeast, and mammalian cells in culture for the past 30 years. Over this time, numerous advances have been made, from using fields to facilitate cell fusion, delivery of chemotherapeutic drugs to cells and tissues, and most importantly, gene and drug delivery in living tissues from rodents to man. Electroporation uses electrical fields to transiently destabilize the membrane allowing the entry of normally impermeable macromolecules into the cytoplasm. Surprisingly, at the appropriate field strengths, the application of these fields to tissues results in little, if any, damage or trauma. Indeed, electroporation has even been used successfully in human trials for gene delivery for the treatment of tumors and for vaccine development. Electroporation can lead to between 100 and 1000-fold increases in gene delivery and expression and can also increase both the distribution of cells taking up and expressing the DNA as well as the absolute amount of gene product per cell (likely due to increased delivery of plasmids into each cell). Effective electroporation depends on electric field parameters, electrode design, the tissues and cells being targeted, and the plasmids that are being transferred themselves. Most importantly, there is no single combination of these variables that leads to greatest efficacy in every situation; optimization is required in every new setting. Electroporation-mediated in vivo gene delivery has proven highly effective in vaccine production, transgene expression, enzyme replacement, and control of a variety of cancers. Almost any tissue can be targeted with electroporation, including muscle, skin, heart, liver, lung, and vasculature. This chapter will provide an overview of the theory of electroporation for the delivery of DNA both in individual cells and in tissues and its application for in vivo gene delivery in a number of animal models.

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Electroporation-Mediated Gene Delivery of Na+,K+-ATPase, and ENaC Subunits to the Lung Attenuates Acute Respiratory Distress Syndrome in a Two-Hit Porcine Model

Cited by 26 publications

References 35 publications

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Vascular Accessibility of Endothelial Targeted Ferritin Nanoparticles

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

Electroporation-Mediated Gene Delivery

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