Novel AAV Variants for Diabetic Macular Edema

用于治疗糖尿病黄斑水肿的新型 AAV 变体

• 批准号: 8394726
• 负责人: Thomas W Chalberg
• 金额: $ 25.99万
• 依托单位: AVALANCHE BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394726
• 关键词: Age; Age related macular degeneration; Albumins; American; Angiogenic Peptides; Area; Binding; Blindness; Blood Vessels; Cells; Clinic; Clinical Research; Clinical Trials; Data; Dependovirus; Development; Diabetes Mellitus; Diabetic Retinopathy; Dyes; Enzyme-Linked Immunosorbent Assay; Exhibits; Extravasation; Eye; Fluorescein-5-isothiocyanate; Generations; Gliosis; Glucose; Growth Factor Inhibition; Human; Immunohistochemistry; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Intraperitoneal Injections; Lasers; Leber' s amaurosis; Libraries; Measures; Mediating; Modeling; Mus; Mutation; Operative Surgical Procedures; Outcome; Patients; Pharmacotherapy; Phase; Photoreceptors; Play; Proteins; Public Health; RPE65 protein; Rattus; Retina; Retinal; Retinal Ganglion Cells; Retinal Neovascularization; Role; Safety; Sampling; Serotyping; Serum; Specificity; Streptozocin; Technology; Therapeutic; Tracer; Transfection; United States; Variant; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Visual; Work; adeno-associated viral vector; aqueous; base; cell type; cellular transduction; clinical application; diabetic; gene therapy; improved; in vivo; inhibitor/antagonist; innovation; intravitreal injection; macular edema; minimally invasive; mutant; neovascularization; novel; phase 2 study; programs; relating to nervous system; research study; restoration; social; standard of care; subretinal injection; success; vector; virus tropism

DESCRIPTION (provided by applicant): The objective of this proposal is to examine the efficacy of novel adeno-associated virus (AAV) variants expressing soluble FLT-1, a potent inhibitor of VEGF-mediated neovascularization and vascular permeability, to treat diabetic macular edema (DME). DME is an advanced form of diabetic retinopathy and the leading cause of blindness among working-age Americans, representing a large and growing public health problem in the United States. Vascular endothelial growth factor (VEGF) is known to play a central role in the progression of diabetic retinopathy and is a potent inducer of vascular permeability. Pharmacotherapy using anti-VEGF agents, which has shown superiority to thermal laser in large clinical trials, is emerging as a new standard of care in the treatment of DME. Although these VEGF inhibitors provide a meaningful advance over previous therapies, the need for frequent intravitreal administrations represents a major shortcoming. AAV has emerged as a proven vector for clinical applications of ocular gene therapy and represents a promising strategy for long-term, sustained delivery of proteins to the eye. Despite its success in early clinical trials, AAV tropism limits its utility for numerous applications in the eye. The developmet of AAV variants capable of efficiently transducing the entire retina following a minimally invasive intravitreal injection would enable further applications in the clinic. We are developing soluble Flt-1 (sFLT), a highly potent (~10 pM) and naturally occurring anti- angiogenic peptide that binds and inactivates VEGF. In our preliminary data, we have identified novel AAV variants that can transfect specific cell types in the retina with high efficiency and specificity following intraviteal administration. In this Phase I proposal, we will quantify levels of sFLT produced by novel AAV variants in vivo. We will also assess and quantify vascular leakage in a rat model of diabetic retinopathy. If this Phase I project demonstrates efficacy of an AAV variant expressing sFLT, these experiments will lay the groundwork for Phase II studies to further substantiate the promise of AAV variants as a treatment for DME. PUBLIC HEALTH RELEVANCE: Diabetic macular edema (DME) is the leading cause of blindness among working-age Americans and a growing public health problem in the United States. VEGF inhibitors are emerging as a new standard of care in treating DME, but require that patients have frequent injections into their eyeball over a period of several years. We propose to develop a therapeutic based on new adeno-associated virus technology that would provide for long-term delivery of anti-VEGF therapeutics in DME without the need for frequent re-injections.

描述（由申请人提供）：该提案的目的是检查表达可溶性FLT-1的新型腺相关病毒（AAV）变体的疗效，这是VEGF介导的新神经血管形成和血管通透性的有效抑制剂，以治疗糖尿病性疾病（DME）。 DME是一种糖尿病性视网膜病的高级形式，也是工人年龄美国人失明的主要原因，代表着美国的大型公共卫生问题。已知血管内皮生长因子（VEGF）在糖尿病性视网膜病的发展中起着核心作用，并且是血管通透性的有效诱导剂。在大型临床试验中，使用抗VEGF药物的药物疗法已显示出对热激光的优越性，它已成为DME治疗的新护理标准。尽管这些VEGF抑制剂比以前的疗法提供了有意义的进步，但频繁玻璃体内管理的需求代表了一个主要的缺点。 AAV已成为眼基因治疗的临床应用的验证载体，并代表了长期，持续蛋白质向眼睛递送的有前途的策略。尽管在早期临床试验中取得了成功，但AAV向流术限制了其对众多应用的实用性。 AAV变体的开发表能够有效地在微创之后有效地转导整个视网膜 玻璃体内注射将在诊所进一步应用。我们正在开发可溶性的FLT-1（SFLT），高度有效（〜10 pm），并且自然存在的抗血管生成肽结合并失活了VEGF。在我们的初步数据中，我们已经确定了新型的AAV变体，这些变体可以在视网膜中以高效率和特异性在视网膜静脉内给药后转染特定细胞类型。在此阶段I建议中，我们将量化新型AAV变体在体内产生的SFLT水平。我们还将评估和量化糖尿病性视网膜病模型中的血管泄漏。如果该阶段I项目表明表达SFLT的AAV变体的功效，则这些实验将为II期研究奠定基础，以进一步证实AAV变体作为DME治疗的希望。 公共卫生相关性：糖尿病性黄斑水肿（DME）是美国人衰老的主要原因，在美国越来越多的公共卫生问题。 VEGF抑制剂正在成为治疗DME的新护理标准，但要求患者在几年内经常注射眼球。我们建议开发基于新的腺相关病毒技术的治疗性，该治疗方法将在DME中长期提供抗VEGF疗法，而无需频繁重新注射。