RdCVF as a novel therapeutic for retinitis pigmentosa

RdCVF 作为色素性视网膜炎的新型治疗方法

• 批准号: 6883431
• 负责人: TIANCI LUO
• 金额: $ 31.18万
• 依托单位: ADVANCED VISION THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883431
• 关键词: biotechnology; biotherapeutic agent; cone cell; enzyme linked immunosorbent assay; gene delivery system; gene therapy; human genetic material tag; human tissue; immunocytochemistry; laboratory mouse; macular degeneration; molecular cloning; polymerase chain reaction; protein structure function; proteins; retinitis pigmentosa; tissue /cell culture; transfection /expression vector; visual photoreceptor; western blottings

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.

高级视觉疗法公司(AVT)正在开发治疗眼疾的新疗法，这种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病、湿性老年性黄斑变性(AMD)和糖尿病增生性视网膜病变，以及视网膜退行性疾病视网膜色素变性 (RP)和干性AMD。AVT已经开发出一种新型的慢病毒基因转移载体，在啮齿动物模型中，只需一次眼内给药，就可以将治疗性蛋白持续输送到视网膜。AVT的战略是将其基因输送系统与有效的治疗性转基因相结合，以快速开发和销售治疗失明疾病的优势产品。作为一种潜在的治疗新生血管疾病的方法，AVT目前正在 评估编码两种有效的抗血管生成剂的载体。然而，识别一种治疗RP和干性AMD的药物更具挑战性。RP和干性AMD的特点是光感受器的进行性丧失，尽管这两种疾病的病理生理学不同。确定一种延长感光细胞寿命的因素，而不考虑导致其加速丧失的机制，可能是一个普遍适用的方法 用于治疗视网膜退行性疾病。最近发现的一种蛋白质，杆源性视锥细胞存活因子(RdCVF)，被证明可以刺激视网膜变性小鼠的视锥细胞存活，并被描述为光感受器存活因子。RdCVF是一种一流的蛋白质，具有巨大的潜力，可以治疗目前无法治疗的一系列视网膜退行性疾病。这一阶段应用的重点是评估RdCVF作为一种潜在的治疗RP和随后的干性AMD的治疗方法。这一关键项目有五个具体目标。1)人RdCVF的克隆。小鼠RdCVF是最近被分离出来的一种109氨基酸分泌蛋白，而人的序列是通过与小鼠蛋白的同源性来鉴定的。将从人视网膜中分离出人蛋白，并对其表达和分泌效率进行评价。2)将开发人RdCVF特异性检测方法。将产生抗体，用于ELISA、Western和免疫组织化学 将建立检测和生物活性检测。3)小鼠和人RdCVF蛋白的体外功能比较。人类蛋白质的预期功能将通过体外光感受器活性测试得到验证，并与老鼠蛋白质的功能进行比较。4)构建编码人和小鼠蛋白质的载体，并进行蛋白质功能的体外验证。5)在相关的视网膜变性小鼠模型Rd1小鼠中进行媒介评估。治疗效益将在视网膜下给药后使用免疫组织化学和定量PCR分析进行评估。第二阶段的研究将集中在RP的目标动物模型中的媒介有效性、临床前安全性研究和媒介制造。I期和II期研究的目的是为IND提交和启动治疗RP的I期临床试验积累足够的数据。