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.

抽象的 青光眼视神经病变（GON）仍然是世界不可逆转的失明的主要原因。现在 时间，唯一可靠的治疗目标是减少眼内压（IOP），这是最普遍的风险 通过药物，激光或手术干预，GON的因素。其中，药理疗法 使用局部眼部掉落单一疗法通常是GON患者选择的初始治疗方法。的 可用的药物类别，前列腺素F2类似物（PGF2α）（例如拉坦前列体）通常被用作首先用作 线疗法。但是，目的地在许多患者中，目的地在减少IOP方面的成功，无反应或侧面治疗 效果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 正常的青光眼眼睛下降。此外，由于药代动力学和剂量方案， IOP中的波动很常见，这也有助于GON。我们最近确定了一个肽马， Stanniocalcin-1（STC-1）局部应用时降低IOP，并且可以以持续的方式表达 使用病毒载体可提供持续的IOP减少。在我们的实验室搜索中确定了STC-1 拉坦前列体介导的IOP还原的下游效应分子。迄今为止，我们已经证明了这一点：1） STC-1是拉坦前列物的降低IOP效应所必需的； 2）主题STC-1降低IOP作为独立的 药物，相当于正常小鼠IOP降低的LatanOprost； 3）STC-1的降低效果 独立于FP受体； 4）STC-1在眼部高血压小鼠中降低IOP； 5）STC-1降低IOP 家猫； 6）由腺相关病毒（AAV-STC-1）传递的STC-1降低了IOP 正常小鼠的时尚。我们针对此应用的中心假设是STC-1的表达 病毒载体将为IOP减少提供有效，安全和持续的治疗 受益于全球遭受青光眼折磨的8000万人。 AIM 1将确认并优化我们的 可以使用病毒载体传递STC-1的初步数据，以持续减少IOP 正常的小鼠。数据将确定IOP还原的最佳病毒载体并与组织相关 表达，定义病毒的最小热剂量，并使用组织学方法评估安全性。 AIM 2意志 利用优化的病毒构建体并评估眼部高血压模型中的IOP降低。类固醇 - 将使用诱导的眼高血压模型以及色素分散的DBA/2J模型。额外的 措施将包括评估水性出口参数。 AIM 3将评估STC-1的病毒表达 在国内和原发性的先天性青光眼猫中，以及评估幽默出口和安全性。 结合强大的初步数据和专家Mentalship小组，这些目标将支持我们的长期 为估计的80估计，开发出小说，有针对性的，持续降低IOP降低剂的术语目标 全世界有百万人与gon。