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In Vivo Hematopoietic Stem Cell Gene Therapy of Beta-Thalassemia

β-地中海贫血的体内造血干细胞基因治疗

基本信息

批准号：
10019196
负责人：
ANDRE Michael LIEBER
金额：
$ 14.89万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019196
关键词：
AMD3100 Adenovirus Vector Adult Back Bone Marrow Bone Marrow Purging Bone Marrow Stem Cell CD34 gene CD46 Antigen CSF3 gene Cells Collection Communicable Diseases DNA DNA cassette Erythroid Erythroid Cells Erythropoiesis Gene Delivery Gene Targeting Gene Transduction Agent Gene Transfer Genes Genetic Genetic Diseases Genomic Segment Globin Goals Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemoglobin Hemolytic Anemia Home environment Human In Vitro Injections Lentivirus Vector Malignant Neoplasms Mediating Modeling Morbidity - disease rate Mus Mutation Patients Production Proteins Proto-Oncogenes Risk Safety Side Site Sleeping Beauty Stream System Systems Integration Testing Thalassemia Therapeutic Time Transfusion Transgenes Transgenic Organisms Transplantation Transposase Ursidae Family base beta Thalassemia cellular transduction cost dimer epigenetic regulation gene therapy genome editing genotoxicity gutless adenoviral vector hematopoietic stem cell expansion homologous recombination in vivo intravenous injection mouse model peripheral blood public health relevance receptor retransplantation transcription activator-like effector nucleases transgene expression vector

项目摘要

DESCRIPTION (provided by applicant) Hematopoietic stem cells (HSCs) are an important target for the gene therapy of infectious diseases, genetic disorders, and cancer. In vivo genome editing of HSCs has major advantages over currently used approaches that involve the collection of HSCs from patients, their in vitro culture/transduction, and retransplantation into myelo-conditioned patients. We have developed a new in vivo approach for HSC transduction, which is based on the GCSF/AMD3100-mediated mobilization of HSCs from the bone marrow into the peripheral blood stream and the intravenous injection of an HSC-targeting, helper-dependent adenovirus vector (HD-Ad5/35). The central goal of this proposal is to increase the percentage of stably in vivo HD-Ad5/35 - transduced HSCs while avoiding potential genotoxicity. We plan to achieve this through i) optimization of HSC mobilization and in vivo HSC transduction, ii) optimization of transgene integration through stimulation of homologous recombination, and iii) incorporation into HD- Ad5/35 vectors of systems that allow for the in vivo selection or expansion of stably transduced cells. Based on these studies, we will generate and test HD-Ad5/35 vectors for in vivo gene therapy of b-thalassemia.

描述（由申请人提供）造血干细胞（HSC）是感染性疾病、遗传性疾病和癌症的基因治疗的重要靶点。HSC的体内基因组编辑相对于目前使用的方法具有主要优势，所述方法涉及从患者收集HSC、其体外培养/转导以及重新移植到骨髓条件患者中。我们开发了一种新的HSC体内转导方法，该方法基于GCSF/AMD 3100介导的HSC从骨髓到外周血流的动员和静脉注射HSC靶向的辅助依赖性腺病毒载体（HD-Ad 5/35）。该提议的中心目标是增加体内稳定HD-Ad 5/35转导的HSC的百分比，同时避免潜在的遗传毒性。我们计划通过i）优化HSC动员和体内HSC转导，ii）通过刺激同源重组优化转基因整合，和iii）将允许体内选择或扩增稳定转导的细胞的系统并入HD-Ad 5/35载体中来实现这一点。基于这些研究，我们将产生和测试用于b-地中海贫血的体内基因治疗的HD-Ad 5/35载体。