Evaluation of novel BIV-based vectors in vivo

Advanced Vision Therapies，Inc. (AVT)正在开发治疗眼部疾病的新疗法，这些疾病是发达国家失明的主要原因。这些疾病包括湿性年龄相关性黄斑变性、糖尿病增殖性视网膜病变和糖尿病黄斑水肿。疾病病理生理学的特征在于脉络膜或视网膜的异常新生血管形成，导致血管渗漏和出血，并最终导致失明。然而，专注于抑制这一过程的疗法在临床试验中显示出希望;这些疗法必须反复直接注射到眼睛中。需要一个更好的交付系统。AVT的策略是将其基因递送系统与新的和有效的抗血管生成转基因相结合，以快速开发和销售用于治疗以下疾病的上级产品： 眼部疾病AVT开发了一种基于牛免疫缺陷病毒（BIV）的最先进的基因传递系统，BIV是一种不会引起人类疾病的牛慢病毒。在啮齿动物模型中，AVT载体表现出对RPE细胞的有效和特异性转导，表达持续至少9个月。当与抗血管生成转基因组合时，在眼部疾病的转基因小鼠模型中有效地阻断了视网膜新生血管形成。然而，啮齿类动物的眼睛与灵长类动物的眼睛有显著不同，因此，这些研究对人类疾病的预测价值尚不清楚。因此，在开始临床试验之前，在灵长类动物模型中评估AVT载体至关重要。这个关键的I期项目将在两种灵长类动物模型、猴体内和人类器官培养中评估AVT载体，并且具有三个具体目标：1）评估视网膜转导效率， 细胞类型特异性和非人灵长类动物中转基因表达的持续时间。编码绿色荧光蛋白（GFP）的AVT载体将通过视网膜下递送给食蟹猴，并通过几项体内和组织学分析监测GFP表达。2)建立人视网膜器官培养以评估AVT载体转导效率和细胞类型特异性。将对健康和患病组织进行评价。灵长类动物数据将用于验证啮齿类动物模型，并提供启动临床试验的关键数据。3)在啮齿动物中建立“故障安全”方案，以允许特异性激光介导的转导RPE细胞消融。如果出于任何原因需要终止治疗性基因表达，则将使用该故障安全装置。II期研究将包括在非人灵长类动物中的AVT载体功效研究、在啮齿动物和猴模型中开始临床前安全性研究、在人视网膜培养物中评估治疗性gone表达以及在非人灵长类动物中评估故障安全策略。这些研究的目的是为IND提交和启动I期临床试验积累足够的数据。

Advanced Vision Therapies, Inc. (AVT) is developing novel therapies for ocular disorders that are the major causes of blindness in the developed world. These diseases include wet age-related macular degeneration, diabetic proliferative retinopathy, and diabetic macular edema. Disease pathophysiology is characterized by abnormal neovascularization of the choroid or retina resulting in vessel leakage and hemorrhage, and ultimately to blindness. Therapies focused on inhibiting this process are showing promise in clinical trials however; these therapeutics must be repeatedly injected directly into the eyes. A better delivery system is needed. The AVT strategy is to combine its gene delivery system with novel and potent anti-angiogenic transgenes to rapidly develop and market a superior product for treatment of ocular disease. AVT developed a state-of-the-art gene delivery system based on the bovine immunodeficiency virus (BIV), a bovine lentivirus that does not cause human disease. In rodent models, the AVT vector demonstrated efficient and specific transduction of RPE cells, with expression sustained for at least nine months. When combined with an anti-angiogenic transgene, retinal neovascularization was effectively blocked in a transgenic mouse model of ocular disease. However, the rodent eye is significantly different than the primate eye, thus, the predictive value of these studies to human disease is not clear. Therefore, it is critically important to assess the AVT vector in primate models, prior to initiation of a clinical trial. This pivotal Phase I project will assess the AVT vector in two primate models, in vivo in monkeys, and in human organ culture, and has three specific aims: 1) Evaluation of retinal transduction efficiency, cell-type specificity, and duration of transgene expression in non-human primates. An AVT vector encoding green fluorescent protein (GFP) will be delivered subretinally to cynomolgus monkeys, and GFP expression will be monitored through several in vivo and histological analyses. 2) Establishment of human retina organ culture to assess AVT vector transduction efficiency and cell-type specificity. Both healthy and diseased tissue will be evaluated. The primate data will serve to validate the rodent models, and provide data critical to the initiation of a clinical trial. 3) Establishment of a "fail-safe" protocol in rodents to allow specific, laser-mediated ablation of the transduced RPE cells. This fail-safe will be utilized if, for any reason, termination of therapeutic gene expression is warranted. Phase II studies will include AVT vector efficacy studies in non-human primates, initiation of preclinical safety studies in rodent and monkey models, assessment of therapeutic gone expression in human retina culture, and evaluation of the fail-safe strategy in non-human primates. The objective of these studies will be to accrue sufficient data for IND submission and initiation of a Phase I clinical trial.