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（由申请方提供）：NVAMD Niranjan B的玻璃体内椭球颗粒的长期抗血管生成活性。Pandey博士- PI Aleksander S. Popel博士- Co-I Jordan J.绿色博士- Co-I Peter A. Campochiaro医学博士- 子项目总结的共同I：目前治疗湿性年龄相关性黄斑变性（AMD）的靶向血管内皮生长因子（VEGFA和胎盘生长因子PlGF）。这些包括Ranibizumab和Aflibercept。雷珠单抗靶向所有形式的VEGFA，而阿柏西普也靶向两种形式的PlGF。然而，这些药物不能改善60-65%的AMD患者的视敏度，表明其他非VEGF/PlGF途径在这些患者中是活跃的。雷珠单抗每月玻璃体内给药，而阿柏西普在每月注射3个月后每两个月给药一次。每月注射增加了感染的风险，对患者来说是负担。最近，与雷珠单抗相比，aflibercept进入AMD市场的速度很快，患者已经显示出他们希望改用更少的注射。最后，雷珠单抗和阿柏西普虽然有效，但不引起现有新血管的消退，仅抑制新血管的生长，因此限制了它们的功效。因此，存在未满足的医疗需求，以靶向对当前疗法无反应的患者，甚至更多地延长玻璃体内施用之间的时间以实现成本节约并减少副作用，以及可以逆转患者疾病症状的药剂。我们建议开发一种肽治疗剂，可以满足这种医疗需求。我们已经开发出一种创新的长椭圆形微粒（微鱼雷），它可以封装各种有效载荷，并且由于其特殊的聚合物设计和抗吞噬形状，预计在眼睛中的寿命很长。抗血管生成肽可以在VEGF和非VEGF生长因子存在下阻断血管生成。本研究拟将这两种技术联合收割机结合起来，设计并制备一种微鱼雷，并将我们的抗血管生成仿生肽（来源于Ⅳ型胶原的β 5纤维）封装在其中。我们提供的数据显示肽在2种广泛使用的AMD小鼠模型中的有效功效，并且数据显示肽的类似物导致新生血管的消退，并且显示对视网膜脱离的有希望的抑制。我们的治疗性微型鱼雷设计用于体内长半衰期，将解决我们着手解决的所有3个问题：它们将在6个月的时间内释放肽，从而将玻璃体内注射的频率从每年12次减少到每年2次，释放的肽将由于其作用机制而同时抑制多种血管生成信号传导途径，并且所述肽还将引起现有的新血管系统的消退，从而潜在地逆转疾病的症状。任何引入这一领域的新药都应该在头对头体内模型中表现得比aflibercept更好，才能在商业上可行;因此，我们建议在我们所有的体内研究中与aflibercept相比，测试我们的治疗方法。