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：
10388103
负责人：
David Terry Curiel
金额：
$ 37.01万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388103
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障碍，例如血友病和α1-抗抗蛋白酶（AAT）缺乏症被认为是矫正基因治疗的理想候选者。在这方面，病毒载体介导的翻译已经提出了许多此类疾病，其中肝细胞代表正常生理缺乏血清因子的来源。具体而言，基于腺体相关的病毒（AAV）的载体具有在动物模型中证明了血友病中的效用，并且将这种方法转化为上下文人类临床试验。尽管有这些发现，但许多考虑因素导致人们认识到可能需要替代矢量方法。首先，与矢量相关的肝毒性使得考虑需要的血清因子的非羊皮化采购。另外，对于某些遗传缺陷诸如AAT缺乏症之类的疾病，AAV介导的肝脏体内转移尚未达到足够缺乏血清因子的水平，以实现有效的基因疗法。我们在这里建议测试我们的原创完成原型血清缺乏症的遗传校正的方法 - AAT缺乏肺疾病。我们的技术平台显然会产生广泛的影响。在第一个方面，我们提供技术为全部遗传性血清缺乏障碍范围的新翻译方法的基础。在第二个考虑一下，我们将设计AD作为能够长期基因表达的车辆。这种根本变化重要的向量的功能将大大扩展可以雇用的公用事业范围。