Electroporation-mediated Pulmonary Gene Transfer for Acute Lung Injury

电穿孔介导的肺基因转移治疗急性肺损伤

• 批准号: 8266351
• 负责人: David A Dean
• 金额: $ 69.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266351
• 关键词: Acute; Acute Lung Injury; Adenovirus Vector; Adenoviruses; Adult; Adult Respiratory Distress Syndrome; Aerosols; Affect; Alveolar; Animal Model; Animal Testing; Animals; Biological Assay; Blood Chemical Analysis; Bolus Infusion; Bronchoscopes; Cell Count; Cessation of life; Chest; Clinical; Clinical Trials; DNA delivery; Disease; Drug Formulations; Electrodes; Electroporation; Family suidae; Future; Gene Combinations; Gene Delivery; Gene Expression; Gene Transfer; Genes; Goals; Histology; Human; Inflammatory Response; Injury; Irrigation; Laboratories; Length of Stay; Ligation; Lipids; Liquid substance; Lung; Mediating; Methodology; Methods; Modality; Modeling; Movement; Mus; Na(+)-K(+)-Exchanging ATPase; Neonatal; Newborn Respiratory Distress Syndrome; Non-Viral Vector; Patients; Phase; Physiologic pulse; Plasmids; Polymers; Positioning Attribute; Pre-Clinical Model; Proteins; Pulmonary Edema; Puncture procedure; Rattus; Recombinants; Recommendation; Reporter Genes; Research; Safety; Saline; Sepsis; Series; Severities; Side; Structure of parenchyma of lung; Surface; Syndrome; Techniques; Technology; Testing; Translating; Trauma; Treatment Efficacy; Tube; United States; Viral; Viral Vector; Work; alveolar epithelium; base; clinical application; cytokine; design; efficacy testing; electric field; endotracheal; epithelial Na+ channel; gene therapy; human disease; in vivo; injured; lung injury; mortality; mouse model; non-viral gene delivery; non-viral gene therapy; novel strategies; plasmid DNA; prevent; research study; response; standard of care; success; surfactant; therapeutic gene; vector; viral vector development

PROJECT SUMMARY/ABSTRACT Acute lung injury (ALI), Acute Respiratory Distress Syndrome (ARDS), and Neonatal Respiratory Distress Syndrome (NRDS) are common, devastating clinical syndromes that affect large numbers of adult and neonatal patients (200,000 cases in the US per year) and have up to 40% mortality with the current standard of care. Our ultimate goal is to develop nonviral gene therapy approaches to treat ALI. We have shown that electroporation can be used to transfer genes to lungs with established lung injury and pulmonary edema to treat the disease and lessen the severity of the injury. The method is simple, fast, and safe. In order to move this toward clinical application, we must demonstrate its efficacy and safety in a large animal model that represents the human disease and develop the most simple and safe method possible in order for it to be accepted by clinicians. The highest recommendation for an animal model is good evidence that the results of the study would be similar in a clinical trial To this end, we have recently applied this approach to a group pigs (35-40 kg) using energies less than 0.1 J/kg and have achieved gene transfer to the lungs with no mortality or injury. Our R21 Phase specific aims are to (1) optimize electroporation parameters for safety and gene transfer to the lungs of pigs, (2) evaluate methods of DNA delivery, (3) develop and optimize a bronchoscope-based electrode for lung gene delivery, and (4) determine whether gene transfer of ENaC as well as Na,K-ATPase subunit genes increases efficacy of gene therapy for treatment of lung injury in a mouse model. At the end of the R21 phase, we will have established optimal parameters for gene delivery to the pig lung and have determined the best therapeutic gene combination to treat lung injury in two complementary pig models of ALI. The R33 phase specific aims are (1) evaluate efficacy of electroporation-mediated gene transfer of Na,K-ATPase/ENaC gene subunits to prevent lung injury in a saline lavage model of mild-moderate ALI, (2) determine whethere transfer of these genes can treat pre-existing lung injury in this model, (3) determine whether transfer of these genes can protect from lung injury in a severe sepsis-induced cecal ligation and pucture model of ARDS, and (4) evaluate whether this approach can be used to treat previously established sepsis-induced lung injury in this model. These studies will provide us with the proof-of-principle for transthoracic pulmonary electroporation and establish the safety and efficacy in an two established pre-clinical models. PROJECT NARRATIVE Acute lung injury, Acute Respiratory Distress Syndrome (ARDS), and Neonatal Respiratory Distress Syndrome are common, devastating clinical syndromes that affect an estimated 200,000 adult and neonatal patients each year in the US and have up to 40% mortality with the current standard of care. We have developed a nonviral gene therapy approach using electric fields that can prevent as well as treat existing ARDS in two small animal models. The work proposed in this study will extend these findings to a large animal model to evaluate whether these findings can be translated into larger subjects and ultimately humans. At the end of the study, we will have demonstrated efficacy of this novel approach to treat lung injury in an established pre-clinical model.

项目总结/文摘

项目成果

Microinjecting cells using a constant-flow microinjection system.

使用恒流显微注射系统显微注射细胞。

• DOI: 10.1101/pdb.prot5590
• 发表时间: 2011
• 期刊: Cold Spring Harbor protocols
• 作者: Dean,DavidA;Gasiorowski,JoshuaZ
• 通讯作者: Gasiorowski,JoshuaZ

Airway pressure release ventilation reduces conducting airway micro-strain in lung injury.

• DOI: 10.1016/j.jamcollsurg.2014.09.011
• 发表时间: 2014-11
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
• 影响因子: 5.2
• 作者: Kollisch-Singule, Michaela;Emr, Bryanna;Smith, Bradford;Ruiz, Cynthia;Roy, Shreyas;Meng, Qinghe;Jain, Sumeet;Satalin, Joshua;Snyder, Kathy;Ghosh, Auyon;Marx, William H.;Andrews, Penny;Habashi, Nader;Nieman, Gary F.;Gatto, Louis A.
• 通讯作者: Gatto, Louis A.

Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury.

• DOI: 10.1097/shk.0b013e31827b47bb
• 发表时间: 2013-01
• 期刊: Shock (Augusta, Ga.)
• 作者: Roy S;Habashi N;Sadowitz B;Andrews P;Ge L;Wang G;Roy P;Ghosh A;Kuhn M;Satalin J;Gatto LA;Lin X;Dean DA;Vodovotz Y;Nieman G
• 通讯作者: Nieman G

Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model.

• DOI: 10.1097/shk.0b013e31829efb06
• 发表时间: 2013-09
• 期刊: Shock (Augusta, Ga.)
• 作者: Roy SK;Emr B;Sadowitz B;Gatto LA;Ghosh A;Satalin JM;Snyder KP;Ge L;Wang G;Marx W;Dean D;Andrews P;Singh A;Scalea T;Habashi N;Nieman GF
• 通讯作者: Nieman GF

Is time the missing component in protective ventilation strategies?

时间是保护性通气策略中缺失的组成部分吗？

• DOI: 10.1097/ccm.0b013e31828ce91b
• 发表时间: 2013
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Nieman,Gary;Gatto,LouisA;Marx,William;Habashi,Nader
• 通讯作者: Habashi,Nader