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

这个SBIR第一阶段项目将确定一种新的高风险技术治疗年龄相关性黄斑变性(AMD)的可行性。该技术是一种AAV2介导的重组蛋白的同时表达，在一次注射中抑制关键生长因子血管内皮生长因子A(血管内皮生长因子A)和血小板衍生生长因子B(PDGF-B)。在美国，AMD是导致失明的主要原因。标准的玻璃体内注射抗血管内皮生长因子(抗血管内皮细胞生长因子)(每月注射)在治疗的前3或4个月实现视力的初步改善，随后是持续2年的平台期，然后是随后5年的视力下降。对视网膜重塑的研究为血管内皮生长因子和血小板衍生生长因子在湿性AMD中的重要性提供了初步线索，而在癌症模型上的工作则为寻求抗血管内皮生长因子/PDGF联合治疗湿性AMD提供了动力。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。长期应用血管内皮生长因子抑制和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，并显著减少患者感染、出血、视网膜脱离、纤维化和疼痛的风险。该项目提出了一种AAV2递送载体，用于表达隔离VEGF-A和PDGF-B的受体内受体。主要的创新是开发了一种新的基因疗法，利用双顺反子AAV2载体同时抑制血管内皮生长因子-A和PDGF-B。拟在小鼠身上进行的研究将确定这种每年注射的替代品的潜在商业化可行性，并提供对新生血管性AMD的两种关键介质的长期持续抑制，包括通过PDGF-B阻断减少纤维化(瘢痕形成)的可能性。此外，S阻断细胞内自分泌环路的能力可能补充或提高目前细胞外治疗的疗效，同时避免弥漫性细胞外血管内皮生长因子抑制的神经毒性。这个项目？S创新在2012年获得了专利(美国专利号8,211,864 B2)。该提案将改进产品并开发一种对CNV具有选择性趋向性的改良型AAV病毒，并将非靶标副作用降至最低。拟议的可行性研究目标1和2将为未来对非人类灵长类动物的安全性和有效性研究建立一个基线，这对投资者来说是一个关键的里程碑。AIM 1将涉及AAV2的制造，而AIM 2将使用组织学、荧光血管造影和光学相干断层扫描来评估安全性和有效性。

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.