Retinal Gene Therapy

视网膜基因治疗

基本信息

批准号：
8737639
负责人：
Zhijian Wu
金额：
$ 86.76万
依托单位：
NATIONAL EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8737639
关键词：
Aftercare Age related macular degeneration Angiogenic Proteins Animal Model Biological Assay Birth Clinical Clinical Trials Collaborations Complement Cyst Data Collection Degenerative Disorder Dependovirus Development Diabetic Retinopathy Disease Electroretinography Engineering Evaluation Gene Expression Gene Mutation Gene Transduction Agent Gene Transfer Genes Genetic Glaucoma Goals Hormones Human Inherited Kinetics Knock-in Mouse Knock-out Knockout Mice Laboratories Leber&apos s amaurosis Life Measures Mediating Mexico Modeling Mus Mutation Pathology Phase Prolactin Publishing Research Research Project Grants Retina Retinal Retinal Cone Retinal Degeneration Retinitis Pigmentosa Retinoschisis Testing Therapeutic Toxic effect Vascular Endothelial Growth Factor Receptor Vision X-Linked Retinoschisis XLRS1 protein adeno-associated viral vector base cell type design gain of function gene therapy human subject improved inhibitor/antagonist loss of function macula mouse model mutant neovascular neutralizing antibody novel preclinical efficacy preclinical study retinal rods therapeutic gene vector

项目摘要

1. Preclinical studies for a retinoschisis clinical trial: We have completed a preclinical efficacy study using a self-complementary AAV8 vector carrying a human retinoschisin expression cassette. The GLP-grade vector has been made for a toxicity study starting at September 2013. Assays of vector stability and AAV8 neutralizing antibody have been established for the upcoming toxicity study. 2. Retinitis Pigmentosa due to: RPGR mutation: We have tested the mouse and human RPGR AAV vectors in two mouse models with RPGR deficiency. Both vectors have shown efficacy in the RPGR knock-out model at 18 months post-administration. The data collection on the Rd9 mouse model is ongoing. To develope an RPGR mouse model with a faster retinal degeneration, a knock-in model has been generated. However, this model appears to be another loss-of-function model similar to the two exsiting models and displays a slow retinal degeneration. An AAV-mediated gene transfer strategy is being used to screen for gain-of-function RPGR mutants. RP2 mutation: We have made an AAV8 human RP2 vector and have tested it in an RP2-null mouse model. Cone functions were rescued at 4 months post-administration and this rescue effect lasted 18 months. Improvement of rod functions was not obvious after treatment due to the mouse model's unique degeneration kinetics in which the rod degeneration happens within 1 month of birth but stabilizes thereafter. 3. Improved therapeutics for neovascular diseases: In collaboration with Dr. Carmen Clapp of the Universidad Nacional Autonoma de Mexico, Juriquilla campus, we are examining a novel anti-angiogenic fragment of prolactin, called vasoinhibin, in the context of AAV vectors. AAV vectors encoding vasoinhibin, prolactin, and sFlt-1 (a soluble VEGF receptor fragment that acts as a competitive inhibitor) have been produced and have been tested in an animal model of diabetic retinopathy. These studies have been successful and were published. We have recently optimized the vectors by converting them into the more efficient self-complementary AAV forms. These vectors are being made and will be tested in the animal model.

1。视网膜临床试验的临床前研究：我们使用携带人视网膜素表达盒的自相平均AAV8载体完成了临床前疗效研究。从2013年9月开始，已经对GLP级载体进行了毒性研究。为即将进行的毒性研究建立了载体稳定性和AAV8中和抗体的测定。 2。色素性视网膜炎由于： RPGR突变：我们已经在具有RPGR缺乏的两个小鼠模型中测试了小鼠和人RPGR AAV量。两位载体在管理后18个月都显示出RPGR敲除模型的功效。 RD9鼠标模型上的数据收集正在进行中。为了开发具有更快的视网膜变性的RPGR小鼠模型，已经生成了敲门模型。但是，该模型似乎是类似于两个Exting模型的另一个功能丧失模型，并且显示出缓慢的视网膜变性。 AAV介导的基因转移策略正在用于筛选功能获得的RPGR突变体。 RP2突变：我们制作了AAV8人RP2载体，并在RP2-NULL小鼠模型中测试了它。在管理后4个月时，圆锥功能被救出，这种救援效应持续了18个月。由于小鼠模型独特的变性动力学，在处理后，杆功能的改善并不明显，其中杆变性发生在出生后的1个月内，但此后稳定。 3。改善了新血管疾病的治疗方法：与Juriquilla校园的Nacional Autonoma de Mexico的Carmen Clapp博士合作，我们正在研究AAV载体的新型催乳素片，称为血管肌蛋白的新型抗血管生成片段。编码血管抑制素，催乳素和SFLT-1（可溶性VEGF受体片段的AAV载体，充当竞争性抑制剂）已被产生，并已在糖尿病性视网膜病动物模型中进行了测试。这些研究已经成功并发表了。最近，我们通过将它们转换为更有效的自我平衡AAV形式来优化了向量。这些向量正在制作，并将在动物模型中进行测试。