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

摘要 青光眼视神经病变（GON）仍然是世界上导致不可逆失明的主要原因。目前 目前，唯一可靠的治疗目标是降低眼压 (IOP)，这是最普遍的风险 通过药物、激光或手术干预来治疗 GON。其中，药物治疗 局部滴眼液单一疗法通常是 GON 患者的初始治疗选择。的 在可用的药物类别中，前列腺素 F2 类似物 (PGF2α)，例如拉坦前列素，通常用作首选药物。 线疗法。然而，尽管它成功地降低了许多患者的眼压，但治疗无反应或副作用 效应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 按处方滴青光眼眼药水。此外，由于药代动力学和给药方案， IOP 波动很常见，这也会导致 GON。我们最近发现了一种肽激素， Stanniocalcin-1 (STC-1) 局部应用时可降低眼压，并能以持续的方式表达 与病毒载体一起提供持续的眼压降低。 STC-1 在我们实验室的搜索中被识别出来 拉坦前列素介导的 IOP 降低的下游效应分子。迄今为止，我们已经证明：1) 拉坦前列素的降低眼压作用需要 STC-1； 2) 局部 STC-1 单独使用可降低 IOP 该药物对于降低血压正常小鼠的眼压效果与拉坦前列素相当； 3) STC-1的降低眼压作用 不依赖于 FP 受体； 4) STC-1降低高眼压小鼠的眼压； 5) STC-1 降低 IOP 家猫； 6) 由腺相关病毒 (AAV-STC-1) 递送的 STC-1 可持续降低眼压 正常血压小鼠的时尚。我们对此应用的中心假设是 STC-1 的表达具有 病毒载体将为降低眼压提供有效、安全和持续的治疗方法，有潜力 造福全球8000万青光眼患者。目标1将确认并优化我们的 初步数据表明，STC-1 可以通过病毒载体传递，以持续降低眼压 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，并与组织相关联 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体并评估高眼压模型中眼压的降低。类固醇—— 将使用诱发高眼压模型以及色素分散的DBA/2J模型。附加 措施将包括评估水流出参数。目标 3 将评估 STC-1 的病毒表达 在家养和原发性先天性青光眼猫中进行评估，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型、有针对性、持续递送的降眼压药物，为估计的 80 全球有 100 万人与 GON 在一起。

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.