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：老年性黄斑变性(AMD)和增殖性糖尿病视网膜病变(PDR)是导致失明和视力障碍的主要原因。血管内皮生长因子在新生血管性AMD的发生和发展中起着关键作用，目前的治疗标准是每月眼内注射雷尼比珠单抗(Lucentis(R))，这是一种专门阻断血管内皮生长因子的抗体片段；另外两种血管内皮生长因子结合蛋白贝伐单抗(Avestin(R))和血管内皮生长因子陷阱眼(Eylea(R))提供类似的益处。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、他们的家人和卫生保健系统造成了巨大的负担，并有 随着注射次数的增加，眼内炎造成的严重视力损失也会增加。此外，减少就诊和注射频率的尝试留下了未覆盖的时期，增加了视网膜下纤维化和/或出血的机会，并降低了视力结果。因此，需要提供持续保护的新的持续给药疗法。为了解决这一未得到满足的需求，我们正在开发一种聚合物-药物偶联技术。在初步研究中，我们已经证明阿霉素(DXR)是一种低氧诱导因子-1(HIF-1)的抑制剂，可以强烈地抑制和导致眼部新生血管(NV)的消退，但作用时间短，治疗窗口窄。相反，我们的实验数据显示，一种新型DXR-聚合物偶联物(DXR-PSA-PEG3)的微粒在非常低的DXR剂量下延长了抗血管生成活性。在Rho/血管内皮生长因子转基因小鼠中，直径为0.65微米的颗粒抑制视紫红质启动子驱动光感受器中血管内皮生长因子表达的眼部NV，持续5周，在同一动物模型中，抑制时间是L眼内注射雷比珠单抗10微克/微克的两倍多，雷比珠单抗在人类中的使用浓度相同。使用敏感的方法没有观察到毒性，即使是有效剂量的100倍。我们的初步数据还显示，聚合物颗粒导致多种HIF-1控制的促血管生成因子下调，导致NV的消退(目前的治疗方法仅减少NV的渗漏)。我们假设，对DXR聚合物和微粒大小的修饰将允许在单次眼内注射几个月后抑制眼部NV，而不会造成毒性，这是开发新的治疗新生血管性AMD和缺血性视网膜病变(如糖尿病视网膜病变)的重要一步。在具体目标1中，我们将开发和充分表征新的聚合物和微球配方，这些聚合物和微球配方在体外持续释放DXR-单体结合物的时间比以前长得多。在具体目标2中，我们将确定最大耐受量(MTD)，并对目标1中有希望的配方进行啮齿动物的药代动力学(PK)和安全性研究。在具体目标3中，我们将测试铅配方的有效性，包括有效性持续时间 在眼部NV的动物模型中来自特定的目标2。如果这些临床前研究像预期的那样进行，我们就可以很好地将其转化为临床。