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: 10297638
• 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/10297638
• 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; 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; 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 青光眼视神经病变(GON)仍然是世界上导致不可逆性失明的主要原因。目前 时至今日，唯一可靠的治疗目标是降低眼压，这是最普遍的风险。 通过药物治疗、激光治疗或外科手术治疗。其中，药物疗法 使用局部滴眼液，单一疗法通常是GON患者的初始治疗选择。中的 可用的药物类别，前列腺素F2类似物(PGF2α)，如拉坦前列素，通常用作第一- 线疗法。然而，尽管它在许多患者中成功地降低了眼压，但治疗无反应或副作用- 影响限制了它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 处方中的青光眼滴眼液。此外，由于药代动力学和给药方案， 眼压波动很常见，这也是导致GON的原因之一。我们最近发现了一种多肽激素， Stanniocalcin-1(STC-1)，局部应用时可降低眼压，并可持续表达 使用病毒载体提供持续的眼压降低。STC-1是在我们实验室的研究中发现的 拉坦前列素介导的降眼压的下游效应分子。到目前为止，我们已经证明：1) 拉坦前列素的降眼压作用需要STC-1；2)局部使用STC-1可单独降低眼压 3)STC-1的降眼压作用 不依赖FP受体；4)STC-1降低高眼压小鼠的眼压；5)STC-1降低高眼压小鼠的眼压 家猫；6)腺相关病毒(AAV-STC-1)携带的STC-1可持续降低眼压 在血压正常的小鼠中流行。我们对这一应用的中心假设是STC-1的表达带有 病毒载体将为降低眼压提供一种有效、安全和持续的治疗方法，有可能 造福全球8000万青光眼患者。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传递，以提供持续的眼压降低 血压正常的小鼠。这些数据将确定降低眼压的最佳病毒载体，并与组织相关 表达，定义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和评估高眼压模型的眼压降低。一种类固醇- 将采用诱导性高眼压模型和DBA/2J色素分散模型。其他内容 这些措施将包括评估含水流出参数。AIM 3将评估STC-1的病毒表达 在家猫和原发性先天性青光眼猫身上进行实验，并评估房水流出和安全性。 结合强大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的、有针对性的、持续的降眼压剂，供大约80人使用 全球有数百万人感染了Gon。