Retinal Gene Therapy

视网膜基因治疗

基本信息

批准号：
8938323
负责人：
Zhijian Wu
金额：
$ 90.92万
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/8938323
关键词：
Aftercare Age related macular degeneration Angiogenic Proteins Animal Model Birth Cell model Clinical Clinical Trials Collaborations Complement Complementary DNA Cone Cyst Data Collection Dependovirus Development Diabetic Retinopathy Disease Disease model Electroretinography Engineering Evaluation Gene Expression Gene Mutation Gene Transduction Agent Gene Transfer Genes Genetic Glaucoma Goals Hormones Human Inherited Kinetics 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 Degeneration Retinitis Pigmentosa Retinoschisis Series Stem cells Structure Testing Therapeutic Toxic effect Vascular Endothelial Growth Factor Receptor Vision X-Linked Retinoschisis XLRS1 protein adeno-associated viral vector base cell type design gene therapy gene therapy clinical trial human subject improved inhibitor/antagonist macula mouse model neovascular novel pre-clinical preclinical efficacy preclinical study retinal rods therapeutic gene treatment strategy vector

项目摘要

1. Preclinical studies for an X-linked retinoschisis gene therapy 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. A toxicity study is ongoing and is anticipated to finish in December 2014. 2. Preclinical gene therapy studies for retinitis pigmentosa due to RPGR or RP2 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 18-24 months post-administration. The data collection on the Rd9 mouse model is ongoing. To develop an RPGR mouse model with a faster retinal degeneration, we have generated RPGR knock-out model with an albino background. Characterization of this new disease model is ongoing. 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. Gene therapy for Leber Congenital Amaurosis due to CEP290 mutation Since the size of CEP290 cDNA exceeds the packaging limit of AAV vector, we are seeking several approaches including the use of dual-vector and functional subunit of CEP290 to deliver the therapeutic genes. We have made a series of AAV vectors and have tested them on a mouse model of the disease. We recently identified one vector that is capable of preserving the retinal function and structure of the mouse model. 4. 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 have been made and are being tested in the animal model.

1。用于X连锁视网膜静脉基因治疗临床试验的临床前研究我们已经使用携带人视网膜感染纸盒的自相融合的AAV8载体完成了一项临床前疗效研究。已经制作了GLP级向量。一项毒性研究正在进行中，预计将于2014年12月完成。 2。由于RPGR或RP2突变引起的视网膜炎色素炎的临床前基因治疗研究我们已经在两个具有RPGR缺乏的小鼠模型中测试了鼠标和人RPGR AAV量。两位载体在管理后18-24个月都显示出在RPGR敲除模型中的功效。 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，我们已经生成了具有白化病背景的RPGR敲除模型。这种新疾病模型的表征正在进行中。我们已经制作了AAV8人RP2矢量，并在RP2-NULL小鼠模型中对其进行了测试。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。由于CEP290突变而导致的Leber先天性症基因治疗由于CEP290 cDNA的大小超过了AAV载体的包装极限，因此我们正在寻求几种方法，包括使用双向量和CEP290的功能亚基来传递治疗基因。我们制作了一系列AAV载体，并在疾病的小鼠模型上对其进行了测试。我们最近确定了一个能够保留小鼠模型的视网膜功能和结构的向量。 4。改善了新生血管疾病的治疗疗法在AAV载体的背景下，我们与Juriquilla校园的Nacional Autonoma de Mexico的Carmen Clapp博士合作，研究了一种称为血管衰变的催乳素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。这些矢量已经制成并正在动物模型中进行了测试。