Eicosanoid Gene Therapy

类二十烷酸基因疗法

基本信息

批准号：
7780354
负责人：
Eric M. Poeschla
金额：
$ 37.4万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780354
关键词：
Adherence Agonist Anabolism Animal Model Aqueous Humor Biological Assay Blindness Data Dinoprost Dinoprostone Disease Eicosanoids Elements Engineering Eye Eye diseases Felis catus Functional disorder Funding Gene Delivery Gene Expression Gene Transfer Techniques Genes Glaucoma Goals Human Image In Vitro Knowledge Latanoprost Learning Lentivirus Vector Leukotrienes Life Lipids Macaca fascicularis Messenger RNA Mitotic Modeling PGF receptor Pathway interactions Patients Pharmaceutical Preparations Physiologic Intraocular Pressure Physiological Physiology Primary Open Angle Glaucoma Prostaglandins Research Personnel Role Severities Signaling Molecule Structure System Testing Thromboxanes Time Tissues Toxic effect Trabecular meshwork structure Transgenes anterior chamber aqueous cyclooxygenase 2 disability drug development gene therapy imaging modality in vivo interest nonhuman primate novel prevent progesterone 11-hemisuccinate-(2-iodohistamine)prostaglandin-F synthase public health relevance receptor response success therapeutic transgene tissue culture vector

项目摘要

DESCRIPTION (provided by applicant): This project will provide lentiviral vector-based gene therapy for primary open angle glaucoma (POAG). In the previous funding cycle we established a robust vector platform and experimental capacity for gene delivery to anterior chamber structures involved in aqueous humor dynamics. We showed that lentiviral vectors could effectively and non-toxically transduce the trabecular meshwork and achieve sustained expression commensurate to the chronicity of POAG. Two large animal models were established in the domestic cat and Cynomolgus monkey. Here we have explored the gene therapy potential of eicosanoids, the potent lipid- derived signaling molecules that include the prostaglandins, thromboxanes and leukotrienes. We hypothesize that since PGF21 agonists have proven intraocular pressure (IOP)-lowering activity, we can manipulate prostaglandin physiology in the eye via gene therapy to achieve sustained IOP reduction. In preliminary studies, we engineered a complete prostaglandin biosynthesis and response pathway in vitro and in vivo, with initial focus on cyclooxygenase-2 (COX-2) and on the PGF21 pathway because of its known role in IOP physiology and its successful exploitation as a pharmacologic target (latanoprost and related drugs). We derived synthetic, sequence optimized cDNAs that were essential to overcoming extreme mRNA liability. This gene therapy results in sustained, non-toxic IOP reduction in the cat. We will develop and use lentiviral vectors in tissue culture assays, perfused human donor eyes, and the two animal models to establish a practical, fully translational IOP-reduction gene therapy. Advanced lentiviral vector expression variables and alternative PG pathways will be systematically studied to learn about the effects of eicosanoids on anterior chamber physiology and maximize gene therapy potential. PUBLIC HEALTH RELEVANCE. The project will develop lentiviral vector-based gene therapy for primary open angle glaucoma (POAG). We will determine optimal prostaglandin biosynthesis and response pathways for sustained IOP reduction and we will gain new knowledge about the roles of prostaglandins in the eye.

描述（由申请人提供）：该项目将为原发性开角型青光眼（POAG）提供基于慢病毒载体的基因治疗。在上一个资助周期中，我们建立了一个强大的载体平台和实验能力，用于将基因传递到涉及房水动力学的前房结构。我们表明，慢病毒载体可以有效且无毒地转导小梁网，并实现与 POAG 慢性相称的持续表达。在家猫和食蟹猴身上建立了两个大型动物模型。在这里，我们探索了类二十烷酸的基因治疗潜力，类二十烷酸是一种有效的脂质衍生信号分子，包括前列腺素、血栓素和白三烯。我们假设，由于 PGF21 激动剂已被证明具有降低眼压 (IOP) 的活性，因此我们可以通过基因疗法操纵眼中的前列腺素生理学，以实现持续的 IOP 降低。在初步研究中，我们在体外和体内设计了完整的前列腺素生物合成和反应途径，最初关注环加氧酶-2 (COX-2) 和 PGF21 途径，因为它在 IOP 生理学中的作用已知，并且成功开发为药理靶点（拉坦前列素和相关药物）。我们衍生了合成的、序列优化的 cDNA，这对于克服极端 mRNA 的不利影响至关重要。这种基因疗法可以使猫持续、无毒地降低眼压。我们将在组织培养测定、灌注人类供体眼睛和两种动物模型中开发和使用慢病毒载体，以建立实用的、完全转化的眼压降低基因疗法。将系统地研究先进的慢病毒载体表达变量和替代 PG 途径，以了解类二十烷酸对前房生理学的影响并最大限度地发挥基因治疗潜力。公共卫生相关性。该项目将开发基于慢病毒载体的原发性开角型青光眼（POAG）基因疗法。我们将确定最佳的前列腺素生物合成和持续降低眼压的反应途径，并且我们将获得有关前列腺素在眼睛中的作用的新知识。