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由血管内皮生长因子（VEGF）驱动，并且是角膜移植排斥、创伤、年龄相关性黄斑变性和糖尿病视网膜病变中的关键事件。目前对这些病症的治疗依赖于每月长期注射抗VEGF剂（例如，阿瓦斯汀（R）; Lucentis（R））进入眼睛，伴随着出血和感染的风险。我们建议使用缓释、细胞内、抗血管生成策略来抑制VEGF。该策略使用将VEG受体1或2（分别为Flt-1或KDR）表达向其可溶性同种型转移的吗啉代，基本上抑制膜结合受体表达并增加可溶性“诱饵”受体的表达。该策略对治疗角膜移植排斥反应、黄斑变性等有潜在的益处 和其他眼血管疾病。 在之前的资助期间，我们使用了可生物降解的、无毒的、含有表达抗VEGF分子的质粒的白蛋白纳米颗粒来维持长达6周的血管抑制。我们接下来将通过与转铁蛋白缀合（以促进局部递送）或与精氨酸-甘氨酸-天冬氨酸（RGD）寡肽缀合（以回到新生血管组织）来推进纳米颗粒递送。靶向递送抗血管生成剂以选择性地在新生血管组织中细胞内阻断VEGF是一个显著未满足的医疗需求，因为最近的数据表明，长期使用玻璃体内雷珠单抗（广泛使用的抗VEGF Fab片段，其在细胞外结合VEGF）与2年内发生地图状萎缩的风险为30%相关，7年时风险超过50%。基于上述基本原理，我们的中心假设是：[a]促进可溶性VEGF受体的吗啉代的表达将抑制角膜移植排斥和脉络膜新生血管形成;和[B]纳米颗粒-吗啉代治疗可以减少纤维化或萎缩。我们的具体目标是检验基于上述假设的以下预测：1。吗啉代将抑制角膜移植的血管生成和排斥反应。我们将使用角膜内和结膜下注射以及设计用于穿过角膜上皮的纳米颗粒的局部递送来测试递送。 2.靶向递送吗啉代的纳米颗粒可以在激光诱导和转基因模型中抑制和消退脉络膜新生血管（CNV）3。长期纳米颗粒介导的吗啉代表达抑制角膜移植和脉络膜新生血管中的纤维化并诱导较少的萎缩 这些研究的结果将确定细胞内抗血管生成治疗是否可以抑制角膜排斥和黄斑变性，并证明纳米颗粒用于长期抗血管生成治疗的潜力，无论是通过局部途径用于角膜疾病，还是通过靶向全身递送用于年龄相关的角膜疾病。 黄斑变性这可能会使新的治疗方式，避免目前的护理标准的风险。