Salivary Gland-Based Gene Therapy for Pulmonary Arterial Hypertension

基于唾液腺的肺动脉高压基因治疗

基本信息

批准号：
8608587
负责人：
RAYMOND Louis Benza
金额：
$ 18.01万
依托单位：
ALLEGHENY-SINGER RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608587
关键词：
Address Adverse effects Affect Aftercare Anabolism Animal Model Area Biological Response Modifier Therapy Bioreactors Blood Circulation Cannulations Caregivers Cell membrane Cells Chimeric Proteins Chronic Complex Continuous Infusion DNA Diagnosis Disease Dose Drug Formulations Encapsulated Endocrine Endothelin Receptor Antagonist Enzymes Epoprostenol Gene Delivery Gene Expression Gene Transfer Goals Heart Human Immune response In Vitro Individual Institutes Labyrinth Left Life Lipids Longevity Lung Mammalian Cell Mammals Measures Mechanics Mediating Microbubbles Modality Modeling Oral cavity Organ Outpatients Pancreas Pathway interactions Patients Pneumonectomy Procedures Process Production Progressive Disease Property Prostacyclin synthase Prostaglandins Prostaglandins I Proteins Pulmonary Vascular Resistance Rattus Regimen Reliance Research Salivary Glands Serum Signal Pathway Site Solutions Structure of submaxillary duct Submandibular gland Survival Rate Symptoms System Techniques Technology Testing Therapeutic Thromboxane A2 Transgenes Translating Ultrasonic Therapy Ultrasonography Vascular Endothelium Viral Vector advanced disease base cyclooxygenase 1 design effective therapy gene delivery system gene therapy gene transfer vector in vivo indexing inhibitor/antagonist innovation non-viral gene delivery novel pressure public health relevance pulmonary arterial hypertension research study restoration therapeutic transgene urinary vector viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to design and test a gene therapy strategy for Pulmonary Arterial Hypertension (PAH). PAH is a rare, deadly and incurable disease with a mean survival of 2.8 years from onset of symptoms if left untreated. Of the three classes of approved therapeutics, endothelin receptor antagonists, phospodiesterase inhibitors, and prostacyclins, prostacyclin is the most effective therapy. However, complicated delivery systems and potential side effects associated with the present formulation of prostanoids (e.g. prostacyclin) have deterred some patients and caregivers from instituting this highly effective class of agents. The challenge to be addressed by this proposal is the need for a therapeutic regimen that allows for endogenous production of prostacyclin therapy within the patient's own body, throughout the entire lifetime of the patient. Because prostacyclin can be produced endogenously through expression of the enzyme Prostacyclin Synthase (PGIS), gene therapy has previously shown proof-of-principle efficacy in animal models by enabling endogenous production of prostacyclin and reversal of experimental PAH. This proposal will build upon this concept, but will execute this strategy using newly developed gene transfer technology that obviates the viral gene delivery vectors that have been used in prior studies. Viral vectors have been extremely useful in earlier studies, but have limited duration of expression, and due to host immune response, cannot affect life- long therapy nor can they be re-dosed. Our gene delivery system, which used ultrasound-induced microbubble cavitation to allow entry of non-viral DNA vectors into cells, is thought to evade host immune responses, theoretically allowing re-dosing of the Prostacyclin Synthase therapeutic transgene as a periodic boosters throughout the entire lifespan of the patient. An additional innovation of this proposal toward achieving the field-wide goal of endogenous prostacyclin production is the choice of the salivary glands as the therapeutic biosynthesis site. The salivary glands can be accessed through a bloodless, outpatient procedure, and contain a robust endocrine secretory pathway capable of secreting transgene products into the intravascular space. The encapsulated, fixed volume of the intraductal labyrinth of the salivary glands also allow precise control of the delivery system, making ultrasound-assisted gene transfer (UAGT) far more practical and consistent than has been observed in other organs (e.g. heart or pancreas). A final innovation of this proposal is the first in vivo application of a Cox-1/PGIS fusion protein that produces dramatically higher levels of prostacyclin than PGIS alone. In summary, this project seeks to innovate the enticing idea of PGIS- based gene therapy for PAH aggregating three enabling technologies: 1) a practical, re-dosable gene delivery technique, 2) a novel biosynthesis site (salivary glands) that can be accessed through an outpatient procedure, and 3) a Cox-1/PGIS fusion protein transgene that produces superior levels of prostacyclin therapeutic. The efficacy of this gene therapy strategy will be tested in a highly relevant rat model of severe PAH.

描述（由申请人提供）：该提案的总体目标是设计和测试肺动脉高压（PAH）的基因治疗策略。 PAH是一种罕见，致命和无法治愈的疾病，如果未经治疗，症状发作后的平均生存率为2。8年。在三类批准的治疗剂，内皮素受体拮抗剂，磷酸二酯酶抑制剂和前列环素蛋白中，前列环素是最有效的疗法。然而，与目前的前列腺素配方相关的复杂输送系统和潜在副作用（例如前列腺素）阻止了一些患者和护理人员建立这种高效的药物。该提案要解决的挑战是需要一种治疗方案，该方案允许在患者的整个一生中，可以在患者自己的身体内部内源性产生前列环素治疗。由于前列环蛋白可以通过表达前列环蛋白合酶（PGIS）的表达来内生产生，因此基因治疗先前已通过启用内源性前列腺细胞环蛋白和实验性PAH的逆转来显示动物模型中的原始功效证明。该提案将基于这个概念，但将使用新开发的基因转移技术执行该策略，该技术避免了先前研究中使用的病毒基因输送向量。病毒载体在较早的研究中非常有用，但是表达持续时间有限，并且由于宿主的免疫反应，不能影响寿命长期治疗，也无法重新剂量。我们的基因输送系统使用超声诱导的微泡液允许将非病毒DNA向量进入细胞，被认为可以逃避宿主的免疫反应，从理论上讲，允许将前列环素Synthase synthase疗法疗法转基因重新剂量作为周期性的激增器。病人的寿命。这项提案的另一个创新是实现内源性前列环蛋白产生目标的全场目标是选择唾液腺作为治疗性生物合成部位。唾液腺可以通过无血，门诊手术进入，并包含能够将转基因产物分泌到血管内空间的强大内分泌分泌途径。唾液腺内导管内迷宫的固定体积也允许精确控制递送系统，使超声辅助基因转移（UAGT）比其他器官（例如心脏或pancreas）更实用和一致。该提案的最终创新是COX-1/PGIS融合蛋白的首次在体内应用，该蛋白在前列环素水平上产生的前列环素水平高于PGIS。总而言之，该项目旨在创新基于PGIS的基因疗法的诱人思想，用于汇总三种启用技术：1）一种可实用的，可重新选择的基因递送技术，2）可以访问的新型生物合成网站（唾液腺）通过门诊手术和3）COX-1/PGIS融合蛋白转基因，可产生优质的前列环素治疗水平。该基因治疗策略的功效将在高度相关的严重PAH大鼠模型中进行测试。