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）基因疗法可以为多种血液疾病提供治疗疗法。常规方法基于体内HSC基因转移，并取得了令人鼓舞的结果。但是，高成本和副作用限制了体内HSC基因治疗的患者可及性。我们有开发了一种体内HSC转移方法，涉及HSC动员和静脉内病毒载体注射。这种方法的成本相对较低，而且技术简单性。它可以作为门诊治疗。我们已经证明了它在几种鼠类疾病模型中的安全性和效率， β-丘脑贫血，镰状细胞贫血和血友病A，最近在恒河猴中。和更多的基因治疗产物在地平线上，体内HSC转导的应用可以推断通用对较大的患者人群的治疗。在通往的道路上进一步改善了体内HSC基因疗法临床应用包括更有效的动员协议，完全消除了先天反应静脉注射，更先进的病毒衣壳修饰，绕过预先存在的抗矢量免疫力，改善体内选择方案以及基因转移载体纯化的新方法。在此应用中，我们将成功检验假设，以改善体内HSC基因疗法的方法小鼠模型中的地中海贫血和镰状细胞疾病。然后，我们将验证最好的组合改善Hon-Human隐私。安全，效率，可移植性和低成本是主要的驱动力每个技术单元的设计/优化。