Anti-angiogenic gene therapy of ocular vascular diseases

眼血管疾病的抗血管生成基因治疗

基本信息

批准号：
9909566
负责人：
Wei Li
金额：
$ 22.5万
依托单位：
EVERGLADES BIOPHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909566
关键词：
Adverse effects Affinity Age related macular degeneration Alternative Therapies Angiogenesis Inhibitors Angiogenic Factor Animal Model Antibodies Binding Blindness Businesses Choroidal Neovascularization Clinical Collaborations Combined Modality Therapy Complement Dependovirus Developed Countries Diabetic Retinopathy Disease Dose Elderly Exudative age-related macular degeneration Fab Immunoglobulins Growth Factor Growth Factor Gene Hypoxia In Vitro Injections Investigational Drugs Lasers Ligands Monoclonal Antibodies Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phosphoglycerate Kinase Preclinical Testing Production Proteins Protocols documentation Reagent Resistance Retinopathy of Prematurity Risk Rodent Safety Small Business Innovation Research Grant Technology Testing Tissues Treatment Efficacy VEGFA gene Vascular Diseases Vascular Endothelial Growth Factors Viral Vision Work adeno-associated viral vector angiogenesis antiangiogenesis therapy base combination gene therapy comparative efficacy efficacy testing gene product gene therapy geographic atrophy geographic risk improved inhibitor/antagonist innovation intravitreal injection member mouse model neovascular neutralizing monoclonal antibodies nonhuman primate novel novel therapeutics promoter ranibizumab receptor response secretogranin III side effect synergism targeted treatment vector

项目摘要

Project Summary Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries. All currently approved anti-angiogenic drugs for nAMD, such as ranibizumab and aflibercept, target vascular endothelial growth factor (VEGF) but have limited therapeutic efficacy. Patients with poor response to one anti-VEGF drug are often switched to another VEGF inhibitors due to the lack of approved drugs against other angiogenic pathways. Furthermore, repeated intravitreal injections in anti-VEGF-resistant patients may increase the risk of injection-related ocular complications. A new strategy is to improve the efficacy is to develop novel therapies against VEGF-independent angiogenic factors for alternative or combination therapy. Another strategy to circumvent repetitive intravitreal injections is to develop anti-angiogenesis gene therapy that requires only a single injection for long-lasting efficacy. However, current approach of anti-VEGF gene therapy yielded marginal treatment benefit to complement ranibizumab, possibly because of their similar mechanisms of action. To circumvent these problems, we recently discovered a novel angiogenic factor with high disease selectivity and VEGF-independent mechanisms. We developed a monoclonal antibody (mAb) against this target and demonstrated its high efficacy for anti-angiogenic therapy of CNV. This project is to develop anti-angiogenesis gene therapy against this novel target using an adeno-associated viral (AAV) vector. In Aim 1, we will generate AAV vectors to express an antibody Fab fragments against the novel target and VEGF under the direction of constitutive or hypoxia-inducible promoters and characterize expression, binding and neutralizing activity of Fab fragments in vitro. In Aim 2, we will determine the therapeutic efficacy and safety of these AAV vectors to alleviate CNV in animal models. Additionally, we will investigate combination gene therapy by simultaneously targeting both factors in the same mouse models to define possible synergy and efficacy improvement. Successful implementation of this project will lead to a novel anti-angiogenesis gene therapy that will improve treatment efficacy of CNV and reduce the requirement for monthly intravitreal injection of anti-VEGF protein drugs.

项目摘要与脉络膜新生血管形成（CNV）的新血管年龄相关的黄斑变性（NAMD）是领先的发达国家老年人失明的原因。所有目前批准的抗血管生成药物用于NAMD，例如ranibizumab和Aflibercept，靶血管内皮生长因子（VEGF），但有限治疗功效。对一种抗VEGF药物反应不佳的患者经常改用另一种VEGF 由于缺乏针对其他血管生成途径的批准药物而引起的抑制剂。此外，重复抗VEGF患者的玻璃体内注射可能会增加注射相关眼的风险并发症。一种新的策略是提高功效替代或联合疗法的血管生成因子。绕过重复玻璃体的另一种策略注射是开发抗血管生成基因疗法，该治疗仅需要一次注射才能持久功效。但是，抗VEGF基因疗法的当前方法产生了边际治疗的好处补充ranibizumab，可能是因为它们的作用机理相似。要解决这些问题，最近，我们发现了一种具有高疾病选择性和无关紧要的新型血管生成因子机制。我们针对该靶标开发了一种单克隆抗体（MAB），并证明了其高疗效用于CNV的抗血管生成疗法。该项目是针对这种新颖的抗血管生成基因治疗使用腺相关病毒（AAV）载体的靶标。在AIM 1中，我们将生成AAV矢量以表达针对新目标的抗体fab片段在本构或缺氧诱导启动子的指导下进行VEGF，并表征表达，在体外的结合和中和活性。在AIM 2中，我们将确定治疗功效这些AAV矢量的安全性可以减轻动物模型中的CNV。此外，我们将研究组合基因治疗同时靶向同一小鼠模型中的两个因素，以定义可能的协同作用和功效提高。该项目的成功实施将导致新的抗血管生成基因可以提高CNV治疗效率并减少玻璃体内注射的要求抗VEGF蛋白药。