The Development of Gene Therapy Using SIRT1 Signaling to Treat Chronic Glaucoma

利用 SIRT1 信号传导治疗慢性青光眼的基因疗法的发展

• 批准号: 10085762
• 负责人: Ahmara G. Ross
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085762
• 关键词: Address; American; Area; Astrocytes; Attenuated; Award; Awareness; Biogenesis; Biomedical Technology; Blindness; CX3C Chemokines; Candidate Disease Gene; Cell Survival; Cell physiology; Cells; Cellular Stress; Cellular Structures; Characteristics; Chronic; Clinical Research; Data; Deacetylase; Degenerative Disorder; Development; Diagnosis; Disease; Disease Management; Ensure; Eye; Eye diseases; Funding; Future; Gene Targeting; Genes; Genetic study; Glaucoma; Glial Fibrillary Acidic Protein; Goals; Grant; Growth; Human; Hydrogen Peroxide; Immune; In Vitro; Inflammatory; Institution; Intervention; K-Series Research Career Programs; Lasers; Lead; Location; Mechanical Stress; Medical; Mentors; Metabolic stress; Methods; Microglia; Mitochondria; Modality; Modeling; Molecular; Monitor; Nerve Degeneration; Neuroglia; Normal Cell; Normal tissue morphology; Ophthalmologist; Ophthalmology; Optic Nerve; Optic Nerve Injuries; Optic Neuritis; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic Intraocular Pressure; Physiology; Play; Positioning Attribute; Prevalence; Process; Request for Proposals; Research; Research Design; Research Personnel; Resources; Resveratrol; Retina; Retinal Degeneration; Retinal Ganglion Cells; Role; SIRT1 gene; Sampling; Schedule; Secure; Signal Pathway; Signal Transduction; Stretching; Structure; Supervision; Supporting Cell; Surgical incisions; Techniques; Technology; Testing; Therapeutic; Tissue Sample; Tissues; Viral; Viral Genes; Viral Vector; Vision; Visual; Work; adeno-associated viral vector; base; blind; body system; career; career development; experience; experimental study; gene delivery system; gene therapy; glaucoma surgery; in vivo; in vivo Model; induced pluripotent stem cell; innovation; interest; meetings; mitochondrial dysfunction; mouse model; neuron loss; neuroprotection; new therapeutic target; novel; novel therapeutics; optic nerve disorder; overexpression; patient responsibilities; personalized medicine; preservation; programs; promoter; receptor; retinal progenitor cell; skills; small molecule; standard care; success; vector

PROJECT ABSTRACT Three million Americans have glaucoma with only half of them aware they carry the diagnosis. There is no cure and 10% of patients who with adequate treatment still have vision loss due to inadequate intraocular pressure control and compliance. Gene therapy as an intervention removes the responsibility of patient-driven treatments to address this global burden. The SIRT1 signaling pathway plays a role in visual preservation during optic nerve injury, making an excellent target gene to introduce this concept. This proposal requests support for a mentored career development award for an ophthalmologist with interest in developing cell- specific gene targeting using AAV to treat glaucoma. The expertise of the mentor involves the use of SIRT1 in a glaucoma model based on evidence from other models of optic nerve injury. At the completion of the award period the candidate will gain valuable experience required to propose, construct, and execute experiments in visual research from patient individualized data gained from current studies at UPenn. The candidate’s goal is to lead a research program that addresses a therapeutic need in glaucoma through the use of gene therapy. This skill set offers a novel and rational approach to treat other cells in eye to manage glaucoma in the future. This project is under the supervision of senior investigators at UPenn in the departments of Ophthalmology, Physiology, and the Center for Advanced Retinal and Ocular Therapeutics (CAROT) who will provide resources for candidate’s career development. The plan involves regular scheduled meetings, structured coursework, guidance for support, and innovative and translational scientific aims. All of the mentors have secured funding to provide necessary resources to ensure success of the aims in the proposal. The institution, mentors, and collaborators outlined in this proposal are dedicated to the research and growth of early investigators. This plan will position the candidate for independence and specialized expertise at the end of the award period through execution of the following AIMS: AIM 1) Define the molecular mechanism of SIRT1 pathway on RGCs. We will confirm the role of SIRT1 pathway expression in induced pluripotent stem cell (IPS) derived RGCs from unaffected control patients using cell stress from hydrogen peroxide (H2O2) and a stretch chamber. AIM 2) Determine the role of SIRT1 signaling with small molecular activators and targeted AAV expression in a mouse model of glaucoma. We will evaluate the role of SIRT1 activation using a mouse model of chronic glaucoma. AIM 3) Develop cell specific adenoviral specific gene delivery system for microglia and astrocytes. We will develop the technology to deliver SIRT1 target gene to astrocytes and microglial cells with specific cell promotors using in vivo models of chronic glaucoma.

项目摘要 三百万美国人患有青光眼，但只有一半人知道自己患有青光眼。 治愈，10%的患者在接受充分治疗后，仍因眼内注射不足而导致视力丧失 基因治疗作为一种干预措施消除了患者驱动的责任。 SIRT1 信号通路在视觉保护中发挥着重要作用。 在视神经损伤期间，制作一个优秀的靶基因来引入这一概念。 支持为对细胞开发感兴趣的眼科医生提供指导性职业发展奖 使用 AAV 治疗青光眼的特定基因靶向 导师的专业知识涉及 SIRT1 的使用。 基于其他视神经损伤模型证据的青光眼模型。 在此期间，候选人将获得提出、构建和执行实验所需的宝贵经验 根据宾夕法尼亚大学当前研究获得的患者个性化数据进行视觉研究。 领导一项研究计划，通过使用基因疗法解决青光眼的治疗需求。 该技能组合提供了一种新颖且合理的方法来治疗眼中的其他细胞，以在未来控制青光眼。 该项目由宾夕法尼亚大学眼科高级研究人员监督， 生理学和高级视网膜和眼部治疗中心 (CAROT) 将提供 该计划包括定期安排的、结构化的会议。 所有导师都有课程作业、支持指导以及创新和转化性科学目标。 获得资金以提供必要的资源，以确保提案中的目标取得成功。 本提案中概述的机构、导师和合作者致力于以下领域的研究和发展： 该计划最终将为候选人提供独立性和专业知识。 通过执行以下目标来延长奖励期限： 目的 1) 明确 SIRT1 通路对 RGC 的分子机制 我们将确认 SIRT1 的作用。 使用来自未受影响的对照患者的诱导多能干细胞（IPS）衍生的 RGC 中的通路表达 来自过氧化氢 (H2O2) 和拉伸室的细胞应力。 目的 2) 通过小分子激活剂和靶向 AAV 确定 SIRT1 信号传导的作用 我们将使用小鼠评估 SIRT1 激活的作用。 慢性青光眼模型。 目的3）开发针对小胶质细胞和星形胶质细胞的细胞特异性腺病毒特异性基因传递系统。 将开发将 SIRT1 靶基因传递到特定细胞的星形胶质细胞和小胶质细胞的技术 使用慢性青光眼体内模型的促进者。