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）：本提案的目的是检查表达可溶性FLT-1的新型腺相关病毒（AAV）变体治疗糖尿病性黄斑水肿（DME）的疗效，可溶性FLT-1是VEGF介导的新生血管形成和血管通透性的有效抑制剂。DME是糖尿病视网膜病变的一种晚期形式，是美国工作年龄人群失明的主要原因，代表着美国一个巨大且日益严重的公共卫生问题。血管内皮生长因子（VEGF）在糖尿病视网膜病变的发展中起着重要作用，是一种有效的血管通透性诱导剂。使用抗VEGF药物的药物治疗在大型临床试验中显示出优于热激光，正在成为治疗DME的新标准。虽然这些VEGF抑制剂提供了一个有意义的进步，以前的治疗，需要频繁的玻璃体内给药代表了一个主要的缺点。AAV已成为眼部基因治疗临床应用的经证实的载体，并代表了将蛋白质长期持续递送至眼睛的有前景的策略。尽管其在早期临床试验中取得了成功，但AAV的向性限制了其在眼睛中的许多应用。AAV变异体的开发能够有效地转导整个视网膜后微创 玻璃体内注射将使得能够在临床中进一步应用。我们正在开发可溶性Flt-1（sFLT），这是一种高效（约10 pM）的天然抗血管生成肽，可结合VEGF并使其失活。在我们的初步数据中，我们已经鉴定了新的AAV变体，其可以在卵黄内施用后以高效率和特异性抑制视网膜中的特定细胞类型。在该I期提案中，我们将量化由新型AAV变体在体内产生的sFLT的水平。我们还将评估和量化糖尿病视网膜病变大鼠模型中的血管渗漏。如果该I期项目证明了表达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治疗的前景。 公共卫生关系：糖尿病性黄斑水肿（DME）是美国工作年龄人群失明的主要原因，也是美国日益严重的公共卫生问题。VEGF抑制剂正在成为治疗DME的新标准，但需要患者在几年内频繁注射到他们的眼球中。我们建议开发一种基于新的腺相关病毒技术的治疗剂，该技术将在DME中提供长期的抗VEGF治疗剂，而不需要频繁的重新注射。