Novel Vector Platform for Gene Therapy

用于基因治疗的新型载体平台

基本信息

批准号：
10231536
负责人：
David Terry Curiel
金额：
$ 42.23万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2023-01-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231536
关键词：
Address Adenovirus Vector Adenoviruses Animal Model Antibodies Biological Models CRISPR/Cas technology Capsid Cells Clinical Trials Dependovirus Development Disease Disease model Elastases Endothelium Engineering Evaluation Gene Delivery Gene Expression Gene Transfer Genes Genetic Hemophilia A Hepatocyte Hepatotoxicity Human Immunity Inherited Knock-in Knock-out Liver Lower respiratory tract structure Lung Lung diseases Mediating Methods Modeling Modification Mus Pathway interactions Patients Phenotype Physiological Protein Deficiency Pulmonary Emphysema Serotyping Serum Serum Proteins Source Specificity System Technology Testing Translating Tropism Viral Vector Work alpha 1-Antitrypsin alpha 1-Antitrypsin Deficiency base design efficacy study gene therapy in vivo mouse model new technology novel novel strategies practical application prototype translational approach vector

项目摘要

ABSTRACT Inherited serum deficiency disorders, such as hemophilia and α1-antitrypsin (AAT) deficiency, have been considered ideal candidates for corrective gene therapy. In this regard, viral vector-mediated transduction of the liver has been proposed for a number of such disorders wherein hepatocytes represent the normal physiologic source of the deficient serum factor. Specifically, adeno-associated virus (AAV)-based vectors have demonstrated utility in hemophilia in animal models and this approach is presently being translated to the context of human clinical trials. Despite these findings, a number of considerations have led to the recognition that alternative vector approaches may be required. In the first instance, vector-related liver toxicities make consideration of non-hepatic sourcing of serum factors desirable. In addition, for some inherited deficiency disorders, such as AAT deficiency, AAV-mediated in vivo transduction of the liver has not achieved adequate levels of the deficient serum factor to achieve effective gene therapy. We propose here to test our highly original approach to accomplish genetic correction of a prototype serum deficiency disorders – AAT deficiency lung disease. Our technology platform will clearly have broad field impact. In the first regard, we provide the technical basis for a new translational approaches for the full range of inherited serum deficiency disorders. In the second regard, we will engineer Ad as a vehicle capable of long term gene expression. This fundamental change in this important vector's functionalities will dramatically expand the range of utilities whereby it can be employed.

抽象的遗传性血清缺乏症，如血友病和 α1-抗胰蛋白酶 (AAT) 缺乏症，已被在这方面，病毒载体介导的转导被认为是纠正基因治疗的理想候选者。肝脏已被提议用于治疗许多此类疾病；肝细胞代表正常的生理功能；具体而言，基于腺相关病毒（AAV）的载体具有缺陷的血清因子的来源。在动物模型中对血友病的效用，这种方法目前正在转化为实际情况尽管有这些发现，但许多考虑因素导致人们认识到：首先，可能需要替代的载体方法。此外，对于某些遗传性缺陷，需要考虑血清因子的非肝脏来源。疾病，如 AAT 缺乏，AAV 介导的肝脏体内转导尚未达到足够的水平我们在此建议测试我们高度原创的血清因子水平，以实现有效的基因治疗。完成原型血清缺乏症——AAT 缺乏肺的基因校正的方法我们的技术平台显然会产生广泛的领域影响。首先，我们提供技术。第二个是针对各种遗传性血清缺乏症的新转化方法的基础。就此而言，我们将把Ad设计为能够长期基因表达的载体，这一根本性改变。重要的向量的功能将极大地扩展其可使用的实用程序范围。