Biomaterial Inhibitor of HIF-1 for Prolonged Anti-Angiogenesis in Eye

HIF-1 生物材料抑制剂可长期抗眼部血管生成

基本信息

批准号：
8964295
负责人：
Peter A Campochiaro
金额：
$ 42.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964295
关键词：
1 year old Address Affect Age related macular degeneration Age-Years Angiogenesis Inhibitors Angiogenic Factor Animal Model Animals Avastin Binding Binding Proteins Biocompatible Materials Blindness Blood Vessels Bolus Infusion Caliber Chemicals Clinic Clinic Visits Clinical Trials Data Development Diabetic Retinopathy Disease Progression Dose Down-Regulation Doxorubicin Drug Formulations Drug Kinetics Electroretinography Endophthalmitis Extravasation Exudative age-related macular degeneration Eye FDA approved Family Family health status Fibrosis Frequencies Grant Growth Healthcare Systems Hemorrhage Hexanes Histology Human Immunoglobulin Fragments In Vitro Inflammatory Response Injectable Injection of therapeutic agent Lead Left Life Lucentis Maximum Tolerated Dose Measurement Medical Methods Microspheres Modification Morphology Mus Nuclear Office Visits Outcome Particle Size Patients Pharmaceutical Preparations Photoreceptors Physicians Play Polyethylene Glycols Polymer Chemistry Polymers Positioning Attribute Proteins Retinal Diseases Rhodopsin Risk Rodent Role Safety Saline Solubility System Technology Testing Therapeutic Thick Time Toxic effect Transgenic Mice Translations VEGF Trap Vascular Endothelial Growth Factors Visit Visual Visual impairment Weight angiogenesis antiangiogenesis therapy bevacizumab biodegradable polymer care systems copolymer design efficacy testing hypoxia inducible factor 1 improved inhibitor/antagonist monomer neovascularization novel ocular neovascularization older patient particle preclinical study proliferative diabetic retinopathy promoter public health relevance ranibizumab rho safety study safety testing sebacic acid standard of care surface coating transcription factor

项目摘要

DESCRIPTION: Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR) are major causes of blindness and visual impairment. Vascular endothelial growth factor (VEGF) plays a critical role in the development and progression of neovascular AMD and the current standard of care is monthly intraocular injections of ranibizumab (Lucentis(r)), an antibody fragment that specifically blocks VEGF; two other VEGF binding proteins, bevacizumab (Avastin(r)) and VEGF Trap-eye (Eylea(r)), provide similar benefits. Frequent office visits and injections are necessary to suppress disease progression, however, they also create significant burden on elderly patients, their families, and the health care system, and the risk of severe vision loss from endophthalmitis increases with increased number of injections. Moreover, attempts to reduce visit and injection frequency leave uncovered periods, increasing the chance of subretinal fibrosis and/or hemorrhage and reduced visual outcomes. Therefore, new sustained delivery treatments that provide constant protection are needed. To address this unmet need, we are developing a polymer-drug conjugate technology. In preliminary studies, we have demonstrated that doxorubicin (DXR), an inhibitor of hypoxia-inducible factor-1 (HIF-1), strongly suppresses and causes regression of ocular neovascularization (NV), but has a short duration of action and narrow therapeutic window. In contrast, our pilot data shows that microparticles of a novel DXR- polymer conjugate (DXR-PSA-PEG3) prolong anti-angiogenic activity at very low DXR doses. Particles that are 0.65 µm in diameter suppressed ocular NV in rho/VEGF transgenic mice, in which the rhodopsin promoter drives expression of VEGF in photoreceptors, for 5 weeks, more than twice as long in the same animal model as a 10 µg/µL intraocular injection of ranibizumab, the same concentration used in humans. No toxicity was observed using sensitive methods, even at 100-times the effective dose. Our pilot data also shows that the polymer particles cause down-regulation of multiple HIF-1 controlled pro-angiogenesis factors, leading to regression of NV (current therapies only reduce leaking from NV). We hypothesize that modifications of the DXR-polymer and microparticle size will allow suppression of ocular NV after a single intraocular injection for several months without causing toxicity, an important step in the development of a new treatment for neovascular AMD and ischemic retinopathies such as diabetic retinopathy. In Specific Aim 1, we will develop and fully characterize new polymers and microsphere formulations that release DXR- monomer conjugates continuously in vitro over much longer periods of time than previously achieved. In Specific Aim 2, we will determine the maximum tolerated dose (MTD) and perform pharmacokinetic (PK) and safety studies in rodents on promising formulations from Aim 1. In Specific Aim 3, we will test the efficacy, including the duration of efficacy, of lead formulations from Specific Aim 2 in animal models of ocular NV. If these pre-clinical studies proceed as expected, we are well-positioned for translation into the clinic.

描述：年龄相关性黄斑变性 (AMD) 和增殖性糖尿病视网膜病变 (PDR) 是失明和视力障碍的主要原因，血管内皮生长因子 (VEGF) 在新生血管性 AMD 的发生和进展以及目前的标准中发挥着关键作用。治疗方法是每月眼内注射雷珠单抗（Lucentis(r)），这是一种特异性阻断 VEGF 的抗体片段，即贝伐珠单抗； (Avastin(r)) 和 VEGF Trap-eye (Eylea(r)) 提供类似的益处，需要频繁就诊和注射来抑制疾病进展，然而，它们也给老年患者及其家人和患者带来了沉重负担。医疗保健系统和风险眼内炎引起的严重视力丧失会随着注射次数的增加而增加。此外，尝试减少就诊和注射频率会导致未覆盖的时间增加，从而增加视网膜下纤维化和/或出血的机会并降低视力结果，因此，需要提供持续保护的新的持续治疗。为了解决这一未满足的需求，我们正在开发一种聚合物-药物缀合物技术，在初步研究中，我们已经证明了阿霉素（DXR）是一种缺氧诱导抑制剂。因子 1 (HIF-1) 强烈抑制并导致眼部新生血管形成 (NV) 消退，但作用持续时间短且治疗窗口窄，相反，我们的试验数据表明新型 DXR-聚合物缀合物的微粒（ DXR-PSA-PEG3) 在非常低的 DXR 剂量下延长抗血管生成活性，直径为 0.65 µm 的颗粒可抑制 rho/VEGF 转基因小鼠的眼部 NV。视紫红质启动子驱动光感受器中 VEGF 的表达，持续 5 周，在相同的动物模型中，其时间是 10 µg/µL 雷珠单抗眼内注射的两倍多，与人类使用的浓度相同，使用敏感方法未观察到毒性。即使是有效剂量的 100 倍，我们的试验数据也表明，聚合物颗粒会导致多种 HIF-1 控制的促血管生成因子下调，从而导致 NV 消退（仅限当前疗法）。我们冒险对 DXR 聚合物和微粒尺寸进行修改，可以在单次眼内注射数月后抑制眼部 NV，而不会引起毒性，这是开发新生血管性 AMD 和 NV 的新疗法的重要一步。在特定目标 1 中，我们将开发并充分表征可在体外持续释放 DXR 单体缀合物的新聚合物和微球制剂。在具体目标 2 中，我们将确定最大耐受剂量 (MTD)，并在啮齿动物中对目标 1 中的有希望的制剂进行药代动力学 (PK) 和安全性研究。在具体目标 3 中，我们将进行测试。先导制剂的功效，包括功效持续时间来自眼 NV 动物模型的具体目标 2 如果这些临床前研究按预期进行，我们就可以很好地转化为临床。