In Vivo Hematopoietic Stem Cell Gene Therapy of Beta-Thalassemia and Sickle Cell Disease

β-地中海贫血和镰状细胞病的体内造血干细胞基因治疗

基本信息

批准号：
10456765
负责人：
ANDRE Michael LIEBER
金额：
$ 65.79万
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 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456765
关键词：
Adenoviruses Aftercare Ambulatory Care Blood Cells Bone Marrow Bone Marrow Aspiration Bone Marrow Purging CD46 Antigen CRISPR/Cas technology Capsid Carmustine Cell Transplantation Cells Clinical Communicable Diseases Data Defect Developing Countries Disease model Dose Engineering Erythrocytes Erythroid Cells Erythropoietin Erythropoietin Receptor Evaluation Fetal Hemoglobin Gene Transfer Genes Genetic Globin Goals Harvest Hematological Disease Hematopoietic Stem Cell Mobilization Hematopoietic stem cells Hemoglobinopathies Hemophilia A High Dose Chemotherapy Human IL1R1 gene Immunity Immunologic Deficiency Syndromes Immunotherapy In Vitro Injections Intravenous Knock-out Leukapheresis Life Macaca mulatta Mediating Methods Modification Mus Mutation Outcome Patients Peripheral Pharmacology Phenotype Price Primates Procedures Process Prophylactic treatment Protocols documentation Regimen Risk Safety Series Sickle Cell Anemia Sleeping Beauty Steroids System Technology Testing Thalassemia Time Toxic effect Toxicology Transgenes Transgenic Mice Transposase Viral Vector Virus antagonist base beta Thalassemia cellular transduction cesium chloride chemotherapy clinical application cost cost effectiveness curative treatments cytokine design driving force efficacy study fetal reactivity gene therapy gene transfer vector genome editing gutless adenoviral vector humanized mouse improved in vivo intravenous injection mouse model nonhuman primate patient population pluripotency portability pre-clinical preclinical study preference prevent repaired response side effect stem cell gene therapy stem cell genes thalassemia intermedia therapeutic transgene trait transgene expression vector

项目摘要

Abstract: Hematopoietic stem cell (HSC) gene therapy could provide a curative treatment for a number of blood diseases. The conventional approach is based on ex vivo HSC gene transfer and has achieved encouraging results. However, the high cost and side effects limit the patient accessibility of ex vivo HSC gene therapy. We have developed an in vivo HSC transduction approach involving HSC mobilization and intravenous viral vector injection. The approach is highlighted by its relatively low cost and technical simplicity. It could be provided as an outpatient treatment. We have demonstrated its safety and efficacy in several murine disease models, including β-thalassemia, Sickle Cell Anemia, and hemophilia A, and more recently, in rhesus macaques. With more gene therapy products on the horizon, the application of in vivo HSC transduction could extrapolate genetic treatments to a larger patient population. Further improvements of in vivo HSC gene therapy on the road to clinical application include more effective mobilization protocols, complete elimination of innate responses upon intravenous vector injection, more advanced virus capsid modifications that circumvent pre-existing anti-vector immunity, improved in vivo selection regimens, as well as new methods for purification of gene transfer vectors. In this application, we will successively test hypotheses to improve in vivo HSC gene therapy approaches for thalassemia and Sickle Cell Disease in mouse models. We will then validate the best combination of improvements in hon-human primates. Safety, efficacy, portability, and low costs are the major driving forces in the design/optimization of each technological unit.

抽象的：造血干细胞（HSC）基因疗法可以为许多血液疾病提供治疗方法。传统方法基于离体 HSC 基因转移，并取得了令人鼓舞的结果。然而，高昂的成本和副作用限制了患者接受离体 HSC 基因治疗。开发了一种体内 HSC 转导方法，涉及 HSC 动员和静脉内病毒载体该方法的特点是成本相对较低且技术简单。我们已经在几种小鼠疾病模型中证明了其安全性和有效性，包括β-地中海贫血、镰状细胞性贫血和A型血友病，最近还出现在恒河猴中。更多基因治疗产品即将面世，体内 HSC 转导的应用可以推断遗传进一步改进体内 HSC 基因治疗的道路。临床应用包括更有效的动员方案、完全消除先天反应静脉注射载体，更先进的病毒衣壳修饰，可规避预先存在的抗载体免疫、改进的体内选择方案以及纯化基因转移载体的新方法。在此应用中，我们将陆续测试改进体内 HSC 基因治疗方法的假设然后我们将在小鼠模型中验证地中海贫血和镰状细胞病的最佳组合。人类灵长类动物的安全性、有效性、便携性和低成本的改进是主要驱动力。每个技术单元的设计/优化。