Regulated Transgene Expression in the Retina

视网膜中转基因表达的调控

• 批准号: 7945314
• 负责人: James M Wilson
• 金额: $ 49.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945314
• 关键词: Address; Affect; Age related macular degeneration; Age-Years; Animal Model; Antibodies; Area; Avastin; Blindness; Budgets; Candidate Disease Gene; Canis familiaris; Cells; Clinical; Clinical Trials; Collaborations; Complex; Cues; Dependovirus; Development; Disease; Disease Progression; Drug Kinetics; Engineering; Eye; Eye diseases; Funding; Gene Expression; Gene Transfer; Generic Drugs; Genes; Genomics; Goals; Healthcare Systems; Human; Immune; Immune response; Immunologics; Inherited; Injection of therapeutic agent; Leber' s amaurosis; Life Expectancy; Liquid substance; Mediating; Medical; Methods; Modeling; Monkeys; Mus; Muscle; Occupations; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Property; Proteins; RPE65 protein; Reporter Genes; Retina; Retinal; Retinal Diseases; Safety; Sampling; Satellite Viruses; Serotyping; Sirolimus; Structure of retinal pigment epithelium; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenes; Vascular Endothelial Growth Factors; Viral Vector; Visual; Visual Acuity; Work; base; cell type; design; disability; economic impact; gene therapy; immunogenic; in vivo; mouse model; prevent; promoter; public health relevance; response; small molecule; socioeconomics; subretinal injection; success; therapeutic gene; transcription factor; transgene expression; vector; volunteer

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area of Genomics (area 08) and the specific Challenge Topic is 08-EY-101: Genomics of complex eye diseases. Diseases that affect visual acuity have emerged as potential candidates for gene therapy. Direct injection of viral vectors, such as those based on adeno- associated viruses (AAV), into different compartments of the eye leads to gene transfer and stable transgene expression into various cell types. High level transduction of retinal pigmented epithelial cells and photoreceptors can be achieved following sub-retinal injection of AAV vectors; this approach has been used to treat a congenital form of blindness called Leber congenital amaurosis in animal models and humans. Many other forms of acquired and inherited blindness are potential candidates for gene therapy although in many cases it will be necessary to regulate expression of the transgene so as to assure therapeutic expression without toxicity. This proposal will develop a method for pharmacologically regulating AAV-encoded genes after introduction into the retina for the treatment of the wet form of age-related macular degeneration (AMD). The method is based on the introduction of a gene encoding an antibody to vascular endothelial growth factor (VEGF) under the control of an inducible promoter together with genes encoding an engineered transcription factor that can be activated by a small molecule to specifically enhance expression of the transgene. This method of inducible transgene expression called ARGENT will be developed in retina of mice and monkeys using convenient reporter genes. Studies will be performed with vectors encoding the humanized VEGF antibody called Avastin in mouse models of AMD; these vectors will also be tested in monkeys for safety and pharmacokinetics. Development of the ARGENT system for AMD will provide a platform of gene therapy that can be applied to a broad array of retinal diseases. Funding of this application will create 2 new jobs. Candidates have been identified for these positions as described in the Budget Justification. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is a growing disease: 1.7 million people developed AMD in 1995 while it is projected that 6.3 million will be affected in 2030. The disease is a major cause for visual disability among persons over 60 years of age that with the increase in life expectancy is not only a medical problem but also one with a significant socio-economic impact. This proposal is designed to develop a gene therapeutic that will provide significant medical relief to patients, develop technologies applicable to other indications in the eye and minimize therapeutic interventions and the burden on the healthcare system.

描述（由申请人提供）：此申请涉及基因组学的广泛挑战领域（区域08），具体挑战主题为08-EAY-101：复杂眼疾病的基因组学。 影响视力的疾病已成为基因治疗的潜在候选者。 直接注射病毒载体，例如基于腺相关病毒（AAV）的病毒载体，将眼睛的不同隔室导致基因转移和稳定的转基因表达到各种细胞类型中。 视网膜下注射AAV载体后，可以实现视网膜色素上皮细胞和感光体的高水平转导；这种方法已被用来治疗一种在动物模型和人类中称为Leber先天性症的盲目形式。许多其他形式的获得和遗传的失明是基因治疗的潜在候选者，尽管在许多情况下，有必要调节转基因的表达，以确保没有毒性的治疗表达。该建议将开发一种在引入视网膜后对AAV编码基因进行药理调节的方法，用于治疗与年龄相关的黄斑变性（AMD）的湿形式。该方法基于在控制诱导型启动子的控制下引入编码血管内皮生长因子（VEGF）抗体的基因，以及编码工程转录因子的基因，可以通过小分子激活该基因，以特异性增强转基因表达。 这种称为Argent的诱导转基因表达方法将在小鼠和猴子的视网膜中使用方便的报告基因开发。 研究将使用编码AMD小鼠模型中的人源化VEGF抗体的载体进行。这些载体还将在猴子的安全和药代动力学中进行测试。 AMD的ARGENT系统的开发将提供一个基因治疗平台，可应用于广泛的视网膜疾病。 此应用程序的资金将创建2个新作业。 如预算辩解中所述，已经确定了这些职位的候选人。 公共卫生相关性：与年龄相关的黄斑变性（AMD）是一种疾病：170万人在1995年发展出AMD，而预计将在2030年受到630万次影响。这种疾病是60岁以上视觉残疾的主要原因，因为预期寿命的增加不仅是一种医疗问题，而且还具有重大的社会经济性影响。该建议旨在开发一种基因治疗性，可为患者提供大量的医疗救济，开发适用于眼睛中其他适应症的技术，并最大程度地减少治疗性干预措施以及医疗保健系统的负担。