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: 9256464
• 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/9256464
• 关键词: Address; 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 Kinetics; Electroretinography; Endophthalmitis; Extravasation; Exudative age-related macular degeneration; Eye; FDA approved; Family; Family health status; Fibrosis; Formulation; Frequencies; Grant; Growth; Healthcare Systems; Hemorrhage; Hexanes; Histology; Human; Hydrophobicity; Immunoglobulin Fragments; In Vitro; Inflammatory Response; Injectable; Injection of therapeutic agent; Lead; 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; VEGFA gene; 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：视网膜相关性黄斑变性（AMD）和增殖性糖尿病视网膜病变（PDR）是失明和视力损害的主要原因。血管内皮生长因子（VEGF）在新生血管性AMD的发展和进展中起着关键作用，目前的护理标准是每月眼内注射雷珠单抗（Lucentis（r）），一种特异性阻断VEGF的抗体片段;另外两种VEGF结合蛋白，贝伐单抗（Avastin（r））和VEGF Trap-eye（Eylea（r）），提供类似的益处。频繁的门诊和注射对于抑制疾病进展是必要的，然而，它们也对老年患者、他们的家庭和卫生保健系统造成了重大负担，并且 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，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递送治疗。为了解决这一未满足的需求，我们正在开发一种聚合物-药物偶联技术。在初步的研究中，我们已经证明，阿霉素（DXR），缺氧诱导因子-1（HIF-1）的抑制剂，强烈抑制和眼新生血管（NV）的消退，但具有短的作用时间和狭窄的治疗窗口。相比之下，我们的试验数据显示，新型DXR-聚合物缀合物（DXR-PSA-PEG 3）的微粒在非常低的DXR剂量下延长抗血管生成活性。在rho/VEGF转基因小鼠中，直径为0.65 µm的颗粒可抑制眼部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，在相同的动物模型中，其时间是眼内注射10 µg/µL雷珠单抗（与人体使用的浓度相同）的两倍多。使用敏感的方法，即使在100倍的有效剂量下也没有观察到毒性。我们的试验数据还表明，聚合物颗粒引起多种HIF-1控制的促血管生成因子的下调，导致NV的消退（目前的疗法仅减少NV的泄漏）。我们假设，DXR-聚合物和微粒大小的修改将允许在单次眼内注射几个月后抑制眼部NV而不引起毒性，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制剂，这些制剂在体外连续释放DXR-单体缀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剂量（MTD），并在啮齿动物中对目标1中有前途的制剂进行药代动力学（PK）和安全性研究。在具体目标3中，我们将测试先导制剂的疗效，包括疗效持续时间 来自眼部NV动物模型中的特异性目标2。如果这些临床前研究按预期进行，我们就有能力将其转化为临床。