SBIR Phase I: Dual suppression of VEGF-A and PDGF-B with extended gene therapy for neovascular AMD

SBIR I 期：通过延长基因治疗对 VEGF-A 和 PDGF-B 进行双重抑制，治疗新生血管性 AMD

• 批准号: 1721400
• 负责人: Sarah Molokhia
• 金额: $ 22.5万
• 依托单位: iVeena Delivery Systems
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1721400&HistoricalAwards=false
• 关键词: SBIR; Phase; Dual; suppression; VEGF

This SBIR Phase I project will determine the feasibility of a new high risk technology for treatment of age-related macular degeneration (AMD). The technology is an AAV2-mediated concurrent expression of recombinant proteins to intracellularly suppress the critical growth factors VEGF-A (vascular endothelial growth factor A) and PDGF-B (platelet-derived growth factor) in a single injection. AMD is the leading cause of blindness in the US. The standard of care intravitreal anti-VEGF (anti-vascular endothelial growth factor) injections (injected monthly) achieve an initial improvement in visual acuity in the first 3 or 4 months of treatment is followed by a plateau that persists for 2 years, followed by visual decline over the subsequent 5 years. Studies examining retinal remodeling provided initial clues as to the importance of VEGF and PDGF in wet AMD, while work in cancer models provided an impetus to pursue anti-VEGF/PDGF combination therapy for the treatment of wet AMD. This project will lead to an effective product for the treatment of wet AMD and related diseases. A long-term VEGF inhibition and PDGF suppression without repetitive intravitreal injections would significantly reduce the number of intraocular injections and the risks of infection, bleeding, retinal detachment, fibrosis, and pain for the patient. This project proposes an AAV2-delivery vehicle for expressing intraceptors which sequester VEGF-A and PDGF-B. The primary innovation is the development of a novel gene therapy to concurrently suppress VEGF-A and PDGF-B, using a bicistronic AAV2 vector. The proposed studies in mice will determine feasibility for potential commercialization of this alternative which would be injected annually and provide long-term sustained suppression of the two key mediators of neovascular AMD, including the potential for reduced fibrosis (scarring) with PDGF-B blockade. Further, this therapy?s ability to block intracellular autocrine loops may complement or improve upon the efficacy of current extracellular treatments, while avoiding neurotoxicity of diffuse extracellular VEGF suppression. This project?s innovations earned a patent in 2012 (US Patent No. 8,211,864 B2). The proposal will refine the product and develop a modified AAV virus with selective tropism for CNV and minimize off-target side effects. The proposed feasibility studies Aims 1 and 2 will establish a baseline for future safety and efficacy studies in non-human primates which is a key mile stone for investors. Aim 1 will involve AAV2 manufacture, while Aim 2 will evaluate safety and efficacy, using histology, fluorescein angiography, and optical coherence tomography.

SBIR第一阶段项目将确定一种治疗年龄相关性黄斑变性（AMD）的新的高风险技术的可行性。该技术是AAV 2介导的重组蛋白的同时表达，以在单次注射中细胞内抑制关键生长因子VEGF-A（血管内皮生长因子A）和PDGF-B（血小板衍生生长因子）。 AMD是美国失明的主要原因。标准治疗玻璃体内抗VEGF（抗血管内皮生长因子）注射（每月注射一次）在治疗的前3或4个月内实现视力的初步改善，随后是持续2年的平台期，随后是随后5年的视力下降。检查视网膜重塑的研究提供了关于VEGF和PDGF在湿性AMD中的重要性的初步线索，而在癌症模型中的工作提供了追求用于治疗湿性AMD的抗VEGF/PDGF组合疗法的动力。该项目将导致一种有效的产品，用于治疗湿性AMD和相关疾病。 长期VEGF抑制和PDGF抑制而不重复玻璃体内注射将显著减少眼内注射的次数和患者感染、出血、视网膜脱离、纤维化和疼痛的风险。该项目提出了一种用于表达隔离VEGF-A和PDGF-B的内受体的AAV 2递送载体。主要创新是开发了一种新的基因疗法，使用双顺反子AAV 2载体同时抑制VEGF-A和PDGF-B。 在小鼠中进行的拟议研究将确定这种替代品的潜在商业化的可行性，这种替代品将每年注射一次，并提供对新生血管性AMD的两种关键介质的长期持续抑制，包括PDGF-B阻断减少纤维化（瘢痕形成）的潜力。此外，这种疗法？阻断细胞内自分泌环的能力可以补充或改善当前细胞外治疗的功效，同时避免弥漫性细胞外VEGF抑制的神经毒性。这个项目？公司的创新在2012年获得专利（美国专利号8，211，864 B2）。该提案将改进产品并开发具有CNV选择性向性的修饰AAV病毒，并将脱靶副作用降至最低。 拟议的可行性研究目标1和2将为未来在非人灵长类动物中进行的安全性和有效性研究建立基线，这是投资者的关键里程碑。目标1将涉及AAV 2的生产，而目标2将使用组织学、荧光素血管造影和光学相干断层扫描来评估安全性和有效性。