LCA Gene Therapy in Somatic Cell-Derived Induced Pluripotent Stem Cells

体细胞衍生的诱导多能干细胞中的 LCA 基因治疗

基本信息

批准号：
8580180
负责人：
ERIN R BURNIGHT
金额：
$ 5.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580180
关键词：
Affect Animal Model Automobile Driving Biological Assay Biopsy Blindness Candidate Disease Gene Cells Child Clinical Trials Degenerative Disorder Dependovirus Dermal Disease Disease Progression Disease model Dissection Effectiveness Eye Fibroblasts Gene Proteins Gene Transfer Generations Genes Human In Vitro Inherited Leber&apos s amaurosis Lentivirus Vector Life Mediating Modeling Mus Mutant Strains Mice Mutation Neural Retina Nuclear Pathologic Nystagmus Patients Phase Photoreceptors RPE65 protein Replacement Therapy Research Research Personnel Retina Retinal Retinal Degeneration Skin Somatic Cell Stargardt&apos s disease Stem cells Structure Structure of retinal pigment epithelium Study models Subfamily lentivirinae System Technology Teratoma Testing Therapeutic Therapy Clinical Trials Thick Tissues Transplantation Viral Vector Virus Diseases base cell type gene correction gene replacement gene replacement therapy gene therapy gene transfer vector human disease human subject in vivo induced pluripotent stem cell mouse model pre-clinical precursor cell promoter public health relevance regenerative regenerative therapy retinal progenitor cell stem cell technology stem cell therapy subretinal injection success therapeutic gene transcription factor vector vector-induced

项目摘要

DESCRIPTION (provided by applicant): Leber Congenital Amaurosis (LCA) is the most severe form of inherited retinal degenerative diseases and is characterized by early on-set nystagmus and blindness, generally occurring within the first year of life. 21% of LCA patients carry mutations in the CEP290 gene, implicating it as a major contributor to the disease. Moreover, CEP290-associated LCA is inherited in an autosomal recessive manner, making it a good candidate for gene-replacement therapy. The recent success of a phase I gene therapy trial for LCA also highlights this treatment as a feasible option for LCA patients. Although this disease may be treatable by gene-replacement therapy using viral vectors, the size of CEP290 precludes the current vector system (adeno-associated virus - AAV) from efficiently packaging the gene. An alternative to AAV for ocular gene transfer is lentivirus. The packaging limit is much greater than that of AAV, and thus will accommodate the large CEP290 gene. Moreover, lentiviral vectors can transduce multiple cell types in the eye, including photoreceptors and retinal pigment epithelium - cell types important in the disease progression of LCA. Pre-clinical animal models of LCA will be useful for studying the effectiveness of CEP290-replacement therapy. The CEP290rd16 mouse model carries a homozygous in-frame 897 bp deletion in the Cep290 gene. These mice display early progressive degeneration of the outer segment and reduction in thickness of the outer nuclear layer, which resembles the human disease. In addition to the CEP290rd16 mouse model, generation of tissue specific retinal cell types from patients with CEP290-associated LCA will make a good model for studying the effectiveness of CEP290-replacement therapy. New induced pluripotent stem cell (iPSC)-based technologies are providing researchers with the ability to model and study human disease and therapeutic correction. In this proposal we aim to generate iPSCs and subsequently photoreceptor precursor cells from a mouse model of retinal degeneration as well as patients with CEP290-associated LCA retinal degenerative disorder. These cells will be used both in and ex vivo for the study of therapeutic gene correction using lentiviral vectors and induced pluripotent stem cell technology.

描述（由申请人提供）：Leber先天性症（LCA）是遗传性视网膜退行性疾病最严重的形式，其特征是早期现场的环形震颤和失明，通常发生在生命的第一年内。 21％的LCA患者在CEP290基因中携带突变，这是该疾病的主要因素。此外，与CEP290相关的LCA以常染色体隐性方式遗传，使其成为基因替代疗法的良好候选者。 LCA I期基因治疗试验的最新成功也强调了这种治疗是LCA患者的可行选择。尽管使用病毒载体可以通过基因替代疗法来治疗这种疾病，但CEP290的大小排除了当前的载体系统（腺相关病毒-AAV-AAV），无法有效地包装基因。 AAV的替代方法是慢病毒。包装极限远大于AAV，因此将容纳大型CEP290基因。此外，慢病毒载体可以转导多种细胞类型，包括感光体和视网膜色素上皮 - 在LCA疾病进展中重要的细胞类型。 LCA的临床前动物模型将有助于研究CEP290替代疗法的有效性。 CEP290RD16小鼠模型在CEP290基因中带有纯合子内897 bp缺失。这些小鼠表现出外部片段的早期进行性变性和类似于人类疾病的外核层厚度的减小。除了CEP290RD16小鼠模型外，与CEP290相关LCA患者的组织特异性视网膜细胞类型的产生将是研究CEP290替代治疗的有效性的良好模型。新的诱导多能干细胞（IPSC）的技术正在为研究人员提供建模和研究人类疾病和治疗性矫正的能力。在此提案中，我们旨在从视网膜变性的小鼠模型以及与CEP290相关的LCA视网膜退行性疾病的患者中产生IPSC和随后的感光前体细胞。这些细胞将用于使用慢病毒载体和诱导多能干细胞技术的治疗基因校正研究。