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: 8763866
• 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/8763866
• 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）：