Targeted Morpholino Interference of VEGF Pathways in Ocular Angiogenesis

眼部血管生成中 VEGF 通路的靶向吗啉干扰

• 批准号: 8542453
• 负责人: BALAMURALI K AMBATI
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542453
• 关键词: Age related macular degeneration; Albumins; Alternative Splicing; Arginine; Aspartic Acid; Atrophic; Avastin; Binding; Blindness; Caring; Choroidal Neovascularization; Chronic; Clinical; Code; Complication; Cornea; Corneal Diseases; Corneal Neovascularization; Data; Devices; Diabetic Retinopathy; Elderly; Event; Eye; Eye Injuries; Eyedrops; Fab Immunoglobulins; Fibrosis; Funding; Glycine; Graft Rejection; Hemorrhage; Home environment; Infection; Injection of therapeutic agent; Injury; Intravenous; Introns; Keratoplasty; Lasers; Length; Lucentis; Macular degeneration; Mediating; Medical; Membrane; Messenger RNA; Modality; Molecular; Ocular Vascular Disorder; Oligopeptides; Pathway interactions; Patients; Plasmids; Protein Isoforms; Risk; Route; Silicon Dioxide; Solid Neoplasm; Testing; Tissues; Transferrin; Transgenic Model; Trauma; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Veterans; Vision; angiogenesis; base; corneal epithelium; design; geographic atrophy; high risk; intravenous injection; nanoparticle; neovascular; neovascularization; ocular angiogenesis; prevent; public health relevance; ranibizumab; receptor; receptor expression; retinal angiogenesis; serum sodium transport inhibitor; standard of care; targeted delivery

DESCRIPTION (provided by applicant): Corneal & retinal angiogenesis are driven by vascular endothelial growth factor (VEGF) and are key events in corneal transplant rejection, trauma, age-related macular degeneration, and diabetic retinopathy. Current treatments for these conditions rely on chronic monthly injections of anti-VEGF agents (e.g., Avastin(R); Lucentis(R)) into the eye, with attendant risks of hemorrhage and infection. We propose to suppress VEGF using a sustained-release, intracellular, anti-angiogenic strategy. This strategy uses morpholinos which shift VEG receptor 1 or 2 (Flt-1 or KDR, respectively) expression towards their soluble isoform, essentially inhibitin membrane-bound receptor expression and increasing expression of soluble, "decoy" receptors. This strategy has potential benefit for treating corneal transplant rejection, macular degeneration and other ocular vascular disorders. During the prior funding period, we used biodegradable, nontoxic, albumin nanoparticles containing plasmids expressing anti-VEGF molecules to sustain angioinhibition for up to 6 weeks. We will next advance nanoparticle delivery through conjugation with transferrin (to facilitate topical delivery) or with arginine-glycine- aspartic acd (RGD) oligopeptides (to home to neovascular tissues). Targeted delivery of anti-angiogenics to block VEGF intracellularly selectively in neovascular tissues is a significant unmet medical need as recent data indicate that long-term use of intravitreal ranibizumab (the widely used anti-VEGF Fab fragment, which binds VEGF extracellularly) is associated with a 30% risk of developing geographic atrophy within 2 years and over 50% risk at 7 years. Based on the above rationale, our central hypotheses are that: [a] expression of morpholinos promoting soluble VEGF receptors, will inhibit corneal transplant rejection and choroidal neovascularization; and [b] nanoparticle-morpholino therapy may reduce fibrosis or atrophy. Our specific aims are to test the following predictions based on the above hypotheses: 1. Morpholinos will inhibit angiogenesis and rejection of corneal transplants. We will test delivery using intracorneal and subconjunctival injections, as well as topical delivery of nanoparticles designed to cross the corneal epithelium. 2. Targeted nanoparticles delivering morpholinos can inhibit and regress choroidal neovascularization (CNV) in laser-induced and transgenic models 3. Long-term nanoparticle-mediated expression of morpholinos inhibits fibrosis and induces less atrophy in corneal transplants and choroidal neovascularization. The results of these studies will define whether intracellular anti-angiogenic therapy can inhibit corneal rejection and macular degeneration, and demonstrate the potential of nanoparticles for long-term anti- angiogenic therapy either by topical routes for corneal disease or targeted systemic delivery for age related macular degeneration. These may enable new treatment modalities which avoid the risks of current standard of care.

描述（由申请人提供）： 角膜和视网膜血管生成是由血管内皮生长因子（VEGF）驱动的，是角膜移植排斥，创伤，与年龄相关的黄斑变性和糖尿病性视网膜病的关键事件。目前对这些疾病的治疗方法依赖于慢性每月注射抗VEGF药物（例如Avastin（r）； Lucentis（R））对眼睛的注射，并具有出血和感染的风险。我们建议使用持续的细胞内，抗血管生成策略抑制VEGF。该策略使用形态学，将蔬菜受体1或2（分别为FLT-1或KDR）转移到其可溶性同工型，基本上是抑制素膜结合的受体表达，并增加可溶性的表达，“诱饵”受体。该策略具有治疗角膜移植排斥，黄斑变性的潜在优势 和其他眼血管疾病。 在以前的资金期间，我们使用了表达抗VEGF分子的质粒的可生物降解，无毒的白蛋白纳米颗粒来维持长达6周的血管抑制作用。我们将通过与转铁蛋白（促进局部递送）或精氨酸 - 甘氨酸 - 天际ACD（RGD）寡肽（到新生血管组织的家中）的结合（以促进局部递送）或与精氨酸 - 甘氨酸 - 天际ACD（RGD）偶然递送。有针对性地输送抗血管生成以阻断新血管内组织中的VEGF细胞内的细胞内是一种未满足的医学需求，因为最近的数据表明，长期使用玻璃体内ranibizumab（广泛使用的抗VEGF Fab碎片）（在外细胞外与VEGF结合）与30％的地理含量相关，在7年的风险中与50％的高度相关。基于上述基本原理，我们的中心假设是：促进可溶性VEGF受体的形态学表达将抑制角膜移植排斥和脉络膜新生血管形成； [b]纳米粒子 - 多腓杆疗法可以减少纤维化或萎缩。我们的具体目的是基于上述假设测试以下预测：1。形态学将抑制角膜移植的血管生成和排斥。我们将使用侧面和结膜下注射以及旨在穿越角膜上皮的纳米颗粒的局部递送进行测试。 2。输送形态的靶向纳米颗粒可以抑制和回归激光诱导的和转基因模型中的脉络膜新生血管形成（CNV）3。长期纳米粒子介导的形态介导的形态学的表达抑制纤维化，抑制纤维化并在角膜移植和脉络膜上诱导较少的萎缩。 这些研究的结果将定义细胞内抗血管生成疗法是否可以抑制角膜排斥和黄斑变性，并证明纳米颗粒对长期抗血管生成疗法的潜力是通过局部途径的角膜疾病或针对性的全身性递送的纳米颗粒。 黄斑变性。这些可能使新的治疗方式避免了当前护理标准的风险。