Long-term anti-angiogenic activity of intravitreal ellipsoid particles for NVAMD

玻璃体内椭球颗粒对 NVAMD 的长期抗血管生成活性

• 批准号: 8874222
• 负责人: Niranjan B Pandey
• 金额: $ 7.1万
• 依托单位: ASCLEPIX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874222
• 关键词: Adult; Adverse effects; Affinity; Age related macular degeneration; Angiogenic Factor; Angiogenic Peptides; Animals; Area; Binding; Biomimetics; Blindness; Blood Proteins; Bruch' s basal membrane structure; Chimeric Proteins; Choroidal Neovascularization; Collagen Type IV; Cost Savings; Data; Disease; Doctor of Medicine; Doctor of Philosophy; Doxycycline; Drug Formulations; EGF gene; Encapsulated; Extravasation; Exudative age-related macular degeneration; Eye; Frequencies; Growth Factor; Half-Life; Head; Health; Immunoglobulin Fragments; In Vitro; Infection; Injection of therapeutic agent; Jordan; Lasers; Lead; Left; Life; Liquid substance; Marketing; Measures; Mediator of activation protein; Medical; Modeling; Mus; Opsin; Oryctolagus cuniculus; Pathway interactions; Patients; Peptides; Permeability; Phagocytosis; Pharmaceutical Preparations; Placental Growth Factor; Prolate; Resistance; Retina; Retinal Detachment; Risk; Rupture; Shapes; Signal Pathway; Signal Transduction; Symptoms; Technology; Testing; Tetanus Helper Peptide; Therapeutic; Time; Transgenic Mice; VEGFA gene; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factors; Visual Acuity; angiogenesis; commercialization; design; drinking water; efficacy testing; improved; in vivo; in vivo Model; innovation; intravitreal injection; laser photocoagulation; macula; mouse model; neovascular; neovascularization; neovasculature; new growth; novel; novel therapeutics; particle; peptide analog; ranibizumab

DESCRIPTION (provided by applicant): Long-term anti-angiogenic activity of intravitreal ellipsoid particles for NVAMD Niranjan B. Pandey, Ph.D. - PI Aleksander S. Popel, Ph.D. - Co-I Jordan J. Green Ph.D. - Co-I Peter A. Campochiaro M.D. - Co-I of subaward Project Summary: Current therapies for wet age-related macular degeneration (AMD) target vascular endothelial growth factors (VEGFA, and placental growth factor PlGF). These include Ranibizumab and Aflibercept. Ranibizumab targets all forms of VEGFA while aflibercept also targets both forms of PlGF. However these drugs do not improve visual acuity in 60-65% of AMD patients, suggesting that other non-VEGF/PlGF pathways are active in these patients. Ranibizumab is administered intravitreally monthly while aflibercept is administered bimonthly after 3 months of monthly injections. Monthly injections increase the risk of infections and are burdensome to patients. Recently, patients have shown their desire to switch to fewer injections by the rapid pace with which aflibercept is making inroads into the AMD market compared to ranibizumab. Finally ranibizumab and aflibercept, although effective, do not cause regression of existing neovasculature, only inhibition of the growth of new vasculature, thus limiting their efficacy. Thus, there is an unmet medical need to target patients that do not respond to current therapies, to extend the time between intravitreal administrations even more to achieve cost savings and reduce side effects, and for agents that can reverse the symptoms of the disease in patients. We propose to develop a peptide therapeutic that could fulfill this medical need. We have developed an innovative prolate ellipsoid microrparticle (microtorpedo) that can encapsulate a wide variety of payloads and is expected to be long-lived in the eye because of its particular polymeric design and its phagocytosis-resistant shape. The anti-angiogenic peptide can block angiogenesis in the presence of VEGF and non-VEGF growth factors. Here we propose to combine these two technologies to design and fabricate a microtorpedo packaged with our lead anti-angiogenic biomimetic peptide derived from the �5 fibril of collagen IV. We present data showing potent efficacy of the peptide in 2 widely used mouse models of AMD and data showing that a close analog of the peptide causes regression of the neovasculature and shows promising inhibition of retinal detachment. Our therapeutic microtorpedo which has been designed for a long half-life in vivo will solve all 3 problems we set out to solve: they will relese peptide over a period of 6 months thus reducing the frequency of intravitreal injections from 12 times a year to 2 times a year, the released peptide will inhibit multiple angiogenic signaling pathways simultaneously because of its mechanism of action, and the peptide will also cause regression of the existing neovasculature thus potentially reversing symptoms of the disease. Any new drug introduced into this space should perform better than aflibercept in head-to-head in vivo models to be commercially viable; thus we propose to test our therapeutic compared to aflibercept in all of our in vivo studies.

描述（由适用提供）：NVAMD Niranjan B. Pandey博士的玻璃体内椭圆形颗粒的长期抗血管生成活性。 - Pi Aleksander S. Popel博士-I Jordan J. Green Ph.D. -I Peter A. Campochiarro M.D. - Subaward Project项目摘要：当前与年龄相关的黄斑变性（AMD）目标血管内皮生长因子（VEGFA和胎盘生长因子PLGF）的当前疗法。这些包括ranibizumab和Aflibercept。 Ranibizumab靶向所有形式的VEGFA，而Aflibercept也靶向两种形式的PLGF。但是，这些药物在60-65％的AMD患者中不能提高视力，这表明其他非VEGF/PLGF途径在这些患者中有效。 ranibizumab每月进行玻璃体室内施用，而在每月3个月的注射3个月后，双月左右进行。每月注射会增加感染的风险，并为患者磨损。最近，与Ranibizumab相比，Aflibercept与Aflibercept迈入AMD市场的快速速度相比，患者的愿望更少。最终，雷尼比珠单抗和Aflibercept虽然有效，但并不会引起现有的新血管系统的消退，而只能抑制新脉管系统的生长，从而限制了它们的有效性。这是针对对当前疗法不反应的患者的未满足医疗需求，以延长玻璃体内管理之间的时间，以增加成本节省并降低副作用，以及可以扭转患者疾病症状的药物。我们已经开发了一种创新的椭圆形微粒（微型粒子），该微粒可以封装各种有效载荷，并且由于其特殊的聚合物设计及其耐吞噬作用的形状，预计将在眼中长期存在。抗血管生成肽可以在存在VEGF和非VEGF生长因子的情况下阻断血管生成。在这里，我们建议将这两种技术结合起来，以设计和制造包装的微型固定相关的抗血管生成仿生型肽，这些肽源自胶原蛋白IV的5纤维。我们提供的数据显示，在2种广泛使用的AMD小鼠模型中，胡椒的潜在有效性，数据表明，辣椒的近距离类似物会导致新脉管系统的消退，并显示出对视网膜脱离的有望抑制。 Our therapeutic microtorpedo which has been designed for a long half-life in vivo will solve all 3 problems we set out to solve: they will release peptide over a period of 6 months thus reducing the frequency of intravitreal injections from 12 times a year to 2 times a year, the released peptide will inhibit multiple angiogenic signaling pathways simply because of its mechanism of action, and the peptide will also cause regression of the existing因此，新生血管系统可能会逆转疾病的症状。引入该空间中的任何新药都应该比在体内模型的头对头的余地表现更好，以便于商业上可行。因此，我们建议在所有体内研究中与Afibercep相比，测试我们的治疗性。