Virally expressed Stanniocalcin-1 for long-term intraocular pressure reduction

病毒表达的 Stanniocalcin-1 用于长期降低眼压

• 批准号: 10462675
• 负责人: Gavin W Roddy
• 金额: $ 15.56万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462675
• 关键词: Address; Animal Model; Aqueous Humor; Blindness; Cornea; Data; Dependovirus; Development; Devices; Dinoprost; Dose; Drug Design; Drug Kinetics; Drug Prescriptions; Eye; Eye diseases; Eyedrops; Felis catus; Glaucoma; Goals; Histologic; Hormones; Injections; Intraocular pressure test; Laboratories; Lasers; Latanoprost; Lead; Measures; Mediating; Mentorship; Methodology; Methods; Modeling; Mus; Ocular Hypertension; Operative Surgical Procedures; PGF receptor; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Pigments; Principal Investigator; Procedures; Property; Prostaglandins; Proteins; Receptor Activation; Reducing Agents; Regimen; Research; Risk Factors; STC1 gene; Safety; Serotyping; Signal Pathway; Signal Transduction; Steroids; System; Testing; Therapeutic; Thick; Time; Tissues; Topical application; Training; Variant; Viral; Viral Load result; Viral Vector; Virus; Wild Type Mouse; adeno-associated viral vector; analog; anterior chamber; aqueous; base; compliance behavior; delivery vehicle; improved; in vivo; insight; lacrimal; mouse model; normotensive; novel; ocular surface; optic nerve disorder; peptide hormone; pre-clinical; preclinical study; pressure; primary congenital glaucoma; response; side effect; success; therapeutic target; treatment choice; treatment response

ABSTRACT Glaucomatous optic neuropathy (GON) remains the world’s leading cause of irreversible blindness. At present time, the only reliable therapeutic target is the reduction of intraocular pressure (IOP), the most prevalent risk factor for GON, by means of pharmacologic, laser, or surgical intervention. Of these, pharmacologic therapy with topical eye drop monotherapy is generally the initial treatment of choice for patients with GON. Of the available medication classes, Prostaglandin F2 analogues (PGF2α) such as latanoprost are often used as first- line therapy. However, despite its success in reducing IOP in many patients, treatment non-response or side- effects limit its use in other patients. Furthermore, some studies estimate that less than half of patients use glaucoma eye drops as prescribed. Additionally, because of the pharmacokinetics and dosing regimens, fluctuation in IOP is common which also contributes to GON. We recently identified a peptide hormone, Stanniocalcin-1 (STC-1) that lowers IOP when applied topically and can be expressed in a sustained fashion with a viral vector to provide sustained IOP reduction. STC-1 was identified in our laboratory’s search of downstream effector molecules in latanoprost-mediated IOP reduction. To date, we have demonstrated that: 1) STC-1 is required for the IOP-lowering effects of latanoprost; 2) Topical STC-1 lowers IOP as a stand-alone drug and is equivalent to latanoprost for IOP reduction in normotensive mice; 3) IOP-lowering effects of STC-1 are independent of the FP receptor; 4) STC-1 lowers IOP in ocular hypertensive mice; 5) STC-1 lowers IOP in the domestic cat; and 6) STC-1 delivered by adeno-associated virus (AAV-STC-1) lowers IOP in a sustained fashion in normotensive mice. Our central hypothesis for this application is that expression of STC-1 with a viral vector will provide an effective, safe, and sustained treatment for IOP reduction that has potential to benefit the 80 million people worldwide afflicted by glaucoma. Aim 1 will confirm and optimize our preliminary data that STC-1 can be delivered with a viral vector to provide sustained IOP reduction in normotensive mice. The data will determine the optimal viral vector for IOP reduction and correlate with tissue expression, define minimal therapeutic dose of virus, and evaluate safety using histologic methods. Aim 2 will utilize the optimized viral construct and evaluate IOP reduction in models of ocular hypertension. A steroid- induced ocular hypertension model as well as the DBA/2J model of pigment dispersion will be used. Additional measures will include assessment of aqueous outflow parameters. Aim 3 will evaluate viral expression of STC-1 in domestic and primary congenital glaucoma cats as well as to evaluate aqueous humor outflow and safety. Combined with strong preliminary data and an expert mentorship panel, these aims will support our long- term goal of developing a novel, targeted, sustained delivery of an IOP-lowering agent for the estimated 80 million people worldwide with GON.

摘要 青光眼性视神经病变（GON）仍然是世界上不可逆性失明的主要原因。目前 目前，唯一可靠的治疗目标是降低眼内压（IOP），这是最普遍的风险 通过药物、激光或外科手术干预的方式，其中，药物治疗 局部滴眼液单药治疗通常是GON患者的初始治疗选择。的 现有的药物类别，前列腺素F2类似物（PGF 2 α），如拉坦前列素，通常用作首选药物。 直线疗法然而，尽管它在许多患者中成功地降低了IOP，但治疗无反应或副作用仍然存在。 影响限制了其在其他患者中的使用。此外，一些研究估计，不到一半的患者使用 青光眼滴眼液处方。此外，由于药代动力学和给药方案， IOP的波动是常见的，这也有助于GON。我们最近发现了一种肽激素， 斯钙素-1（STC-1），局部应用时可降低IOP，并可持续表达 以提供持续的IOP降低。STC-1是在我们实验室的研究中发现的， 拉坦前列素介导的IOP降低中的下游效应分子。到目前为止，我们已经证明：1） STC-1是拉坦前列素降低IOP作用所必需的; 2）局部STC-1作为独立药物降低IOP， 在正常血压小鼠中，STC-1与拉坦前列素在降低IOP方面是等效的; 3）STC-1的降低IOP作用 不依赖于FP受体; 4）STC-1降低高眼压小鼠的IOP; 5）STC-1降低高眼压小鼠的IOP。 和6）腺相关病毒（AAV-STC-1）递送的STC-1以持续的降低IOP的方式降低IOP。 在正常血压的小鼠中，我们对该应用的中心假设是STC-1的表达与 病毒载体将提供有效、安全和持续的IOP降低治疗， 使全球8000万青光眼患者受益。目标1将确认和优化我们的 初步数据表明，STC-1可以与病毒载体一起递送，以提供持续的IOP降低， 血压正常的小鼠。这些数据将确定用于IOP降低的最佳病毒载体，并与组织相关。 表达，确定病毒的最小治疗剂量，并使用组织学方法评估安全性。目标2将 利用优化的病毒构建体并评估高眼压模型中的IOP降低。类固醇- 将使用诱导的高眼压模型以及色素分散的DBA/2 J模型。额外 测量将包括评估房水流出参数。目的3：研究STC-1的病毒表达 在国内和原发性先天性青光眼猫，以及评估房水流出和安全性。 结合强有力的初步数据和专家指导小组，这些目标将支持我们的长期- 长期目标是开发一种新型的、靶向的、持续的降眼压药物， 全世界有100万人与GON合作。