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

• 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
• 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

 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 的发生和进展中起着至关重要的作用，目前的护理标准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；另外两种 VEGF 结合蛋白，贝伐珠单抗 (Avastin(r)) 和 VEGF Trap-eye (Eylea(r))，也具有类似的功效。频繁的就诊和注射对于抑制疾病进展是必要的，然而，它们也给老年患者、他们的家人和医疗保健系统造成了沉重的负担，并且存在感染风险。 眼内炎引起的严重视力丧失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留下未覆盖的时期，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递送治疗。为了解决这一未满足的需求，我们正在开发聚合物-药物缀合物技术。在初步研究中，我们已证明缺氧诱导因子-1 (HIF-1) 抑制剂阿霉素 (DXR) 能够强烈抑制并导致眼部新生血管 (NV) 消退，但作用持续时间短且治疗窗口窄。相比之下，我们的试验数据表明，新型 DXR-聚合物缀合物 (DXR-PSA-PEG3) 的微粒在非常低的 DXR 剂量下可延长抗血管生成活性。直径 0.65 µm 的颗粒可抑制 rho/VEGF 转基因小鼠的眼部 NV，持续 5 周，其中视紫红质启动子驱动光感受器中 VEGF 的表达，在同一动物模型中，是眼内注射 10 µg/µL 雷珠单抗（与人类使用的浓度相同）的两倍多。即使使用有效剂量的 100 倍，使用敏感方法也未观察到毒性。我们的试验数据还表明，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（目前的疗法仅减少 NV 渗漏）。我们假设，对 DXR 聚合物和微粒尺寸的修改将能够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 和缺血性视网膜病（如糖尿病视网膜病）新疗法的重要一步。在具体目标 1 中，我们将开发并全面表征新的聚合物和微球配方，这些配方可在比以前实现的更长的时间内在体外连续释放 DXR-单体缀合物。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 中的有前景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 动物模型中的特定目标 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。