RdCVF as a novel therapeutic for retinitis pigmentosa

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。这些疾病包括新生血管性眼部疾病、湿性年龄相关性黄斑变性（AMD）和糖尿病增殖性视网膜病变，以及视网膜变性疾病、视网膜色素变性 (RP)和干性AMD。AVT已经开发了一种新型的慢病毒基因转移载体，其在单次眼内给药后在啮齿动物模型中向视网膜持续递送治疗性蛋白质。AVT的战略是将其基因递送系统与有效的治疗转基因相结合，以快速开发和销售用于治疗致盲性眼病的上级产品。AVT作为一种治疗新生血管性疾病的潜在方法，目前已被广泛应用于临床， 评价编码两种有效的抗血管生成剂的载体。然而，确定RP和干性AMD的治疗剂更具挑战性。RP和干性AMD的特征在于光感受器的进行性丧失，尽管这两种疾病之间的疾病病理生理学不同。无论导致光感受器加速损失的机制如何，识别将延长光感受器寿命的因素可能是普遍适用的。 用于治疗视网膜变性疾病的治疗剂。最近发现的一种蛋白质，视杆细胞衍生的视锥细胞活力因子（RdCVF），被证明刺激视网膜变性的小鼠模型中的视锥细胞存活，并被描述为感光细胞活力因子。RdCVF是一种一流的蛋白质，具有巨大的潜力，可作为目前无法治疗的各种视网膜退行性疾病的治疗药物。该I期申请的重点是评价RdCVF作为RP和随后的干性AMD的潜在治疗剂。这个关键项目有五个具体目标。1}人RdCVF的克隆。小鼠RdCVF最近被分离为109个氨基酸的分泌蛋白，而人序列通过与鼠蛋白的同源性被鉴定。将从人视网膜cDNA中分离人蛋白质，并评价表达和分泌效率。2)将开发人RdCVF特异性试验。将生成用于ELISA、Western和免疫组织化学的抗体 将建立分析和生物活性分析。3}小鼠和人RdCVF蛋白在体外的功能比较。将使用体外光感受器活力测定验证人蛋白的预期功能，并与小鼠蛋白的预期功能进行比较。4)产生编码人和小鼠蛋白质的载体，并在体外验证蛋白质功能。5)在视网膜变性的相关小鼠模型rd1小鼠中的载体评估。视网膜下给药后，将使用免疫组织化学和定量PCR分析评估治疗益处。II期研究将重点关注RP靶动物模型中的载体功效、临床前安全性研究和载体生产。I期和II期研究的目的是为IND提交和启动RP治疗的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 the neovascular ocular disorders, wet age-related macular degeneration (AMD) and diabetic proliferative retinopathy, and the retinal degenerative disorders, retinitis pigmentosa (RP), and dry AMD. AVT has developed a novel lentiviral gene transfer vector that following a single intra-ocular administration provides sustained delivery of a therapeutic protein to the retina in rodent models. The AVT strategy is to combine its gene delivery system with potent therapeutic transgenes to rapidly develop and market superior products for the treatment of blinding ocular diseases. As a potential therapy for the neovascular diseases, AVT currently is evaluating vectors encoding two potent anti-angiogenic agents. However, the identification of a therapeutic for RP and dry AMD is more challenging. RP and dry AMD are characterized by a progressive loss of photoreceptors, although the disease pathophysiology differs between the two diseases. The identification of a factor that would prolong the life of photoreceptors irrespective of the mechanism leading to their accelerated loss may be a generally applicable therapeutic for the treatment of retinal degenerative diseases. A recently discovered protein, Rod-derived Cone Viability Factor (RdCVF), was demonstrated to stimulate cone survival in a mouse model of retinal degeneration, and was described as a photoreceptor viability factor. RdCVF, a first-in-class protein, has an enormous potential as a therapeutic for a wide range of currently untreatable retinal degenerative disorders. The focus of this Phase I application is the evaluation of RdCVF as a potential therapeutic for RP and subsequently, dry AMD. There are five specific aims to this pivotal project. 1} Cloning of human RdCVF. Mouse RdCVF was recently isolated as a 109 aa secreted protein, while the human sequence was identified through homology to the murine protein. The human protein will be isolated from human retinal cDNA and expression and secretion efficiency evaluated. 2) Human RdCVF-specific assays will be developed. Antibodies will be generated for use in ELISA, Western, and immunohistochemical assays and biological activity assays will be established. 3} Comparison of mouse and human RdCVF protein function in vitro. The expected function of human protein will be verified and compared to that of the mouse protein using an in vitro photoreceptor viability assay. 4) Generation of vectors encoding both the human and mouse proteins, and in vitro verification of protein function. 5) Vector evaluation in a relevant mouse model of retinal degeneration, the rd1 mouse. Therapeutic benefit will be assessed following subretinal administration using immunohistochemical and quantitative PCR analyses. The Phase II studies will focus on vector efficacy in a targe animal model of RP, preclinical safety studies, and vector manufacturing. The objective of the Phase I and II studies is to accrue sufficient data for IND submission and initiation of a Phase I clinical trial for treatment of RP.