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: 8913404
• 负责人: Niranjan B Pandey
• 金额: $ 2.5万
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913404
• 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(由申请人提供)：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的玻璃体内椭球颗粒的长期抗血管生成活性子奖项目摘要：针对目标血管内皮生长因子(VEGFA)和胎盘生长因子PlGF的湿性年龄相关性黄斑变性(AMD)的当前治疗方法。这些药物包括ranibizumab和afLibercept。Ranibizumab针对所有形式的VEGFA，而afLibercept也针对两种形式的PlGF。然而，这些药物并没有改善60%-65%的AMD患者的视力，这表明其他非血管内皮生长因子/PlGF通路在这些患者中是活跃的。雷尼比珠单抗每月玻璃体内注射，而afLibercept在每月注射3个月后每两个月给药一次。每月注射会增加感染的风险，并给患者带来负担。最近，与ranibizumab相比，afLibercept快速打入AMD市场的速度表明，患者希望改用更少的注射。最后，雷尼比珠单抗和阿普利赛特虽然有效，但不会导致现有新生血管的退化，只会抑制新血管的生长，从而限制了它们的疗效。因此，有一种尚未得到满足的医疗需求，即针对对当前治疗无效的患者，进一步延长玻璃体腔给药之间的时间间隔，以实现成本节约和减少副作用，以及寻找能够逆转患者疾病症状的药物。我们建议开发一种能够满足这一医学需求的多肽疗法。我们开发了一种创新的长椭圆形微粒(微型鱼雷)，它可以包裹各种有效载荷，由于其独特的聚合物设计和抗吞噬形状，预计将在眼睛内长期存活。该抗血管生成多肽可以在血管内皮生长因子和非血管内皮生长因子存在的情况下阻断血管生成。在这里，我们建议结合这两种技术来设计和制造一种微型鱼雷，包装上使用我们从IV型胶原的�5纤维中提取的先导抗血管生成仿生肽。我们提供了在两种广泛使用的AMD小鼠模型中展示该肽的有效效果的数据，并且数据表明，与该肽非常相似的多肽可以导致新生血管的消退，并显示出有希望的抑制视网膜脱离的作用。我们设计的治疗微鱼雷在体内有很长的半衰期，它将解决我们计划解决的所有3个问题：它们将在6个月内重新释放多肽，从而将玻璃体内注射的频率从每年12次减少到每年2次，释放的多肽将由于其作用机制同时抑制多个血管生成信号通路，以及多肽还将导致现有新生血管的退化，从而潜在地逆转疾病的症状。任何引入这一领域的新药在头对头的活体模型中都应该比afLibercept表现得更好，才能具有商业可行性；因此，我们建议在我们所有的体内研究中测试我们的治疗方法与afLibercept的比较。