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Enhance AAV Liver Transduction with Capsid Immune Evasion

通过衣壳免疫逃避增强 AAV 肝脏转导

基本信息

批准号：
9893176
负责人：
Chengwen Li
金额：
$ 6.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893176
关键词：
Address Antigen Presentation Antigen Presentation Pathway Antigens Bortezomib Capsid Clinical Clinical Trials Cross Presentation Cytotoxic T-Lymphocytes Data Dependovirus Development Directed Molecular Evolution Dose Failure Felis catus Genes Genome Hemophilia A Hemophilia B Hepatocyte Histocompatibility Antigens Class I Histocompatibility Antigens Class II Human Immune Evasion In Vitro Infection Investigation Ion-Exchange Chromatography Procedure Kinetics Liver Mediating Methods Modification Mus Pathway interactions Patients Phase I Clinical Trials Preparation Proteasome Inhibitor Risk Surface Therapeutic Time Translating Tropism Ubiquitination Virion Virus Work Xenograft Model Xenograft procedure adeno-associated viral vector cellular transduction cesium chloride design gene therapy humanized mouse in vivo insight liver injury liver xenograft mouse model multicatalytic endopeptidase complex mutant particle public health relevance response transduction efficiency vector

项目摘要

DESCRIPTION: Adeno-associated virus (AAV) vector has been successfully applied in phase I clinical trials in hemophilia B patients with liver targeting. However, these studies have suggested that AAV capsid specific cytotoxic T lymphocytes (CTL) have the potential to eliminate AAV transduced hepatocytes and result in the therapeutic failure. Our prior studies have demonstrated that AAV capsid antigen presentation is dose-dependent and requires capsid ubiquitination for proteasome mediated degradation. The contamination of empty virions in AAV preparation inhibits transduction from full particles of AAV vectors and potentially increases the risk of virus capsid antigen load. In this proposal we will investigate capsid antige presentation from AAV empty virions and the effect of empty particles on antigen presentation from full virus transduction (Aim 1). To decrease antigen presentation on AAV transduced cells for avoiding capsid specific CTL-mediated elimination, it has been proposed to modify the AAV capsid surface or apply proteasome inhibitors to enhance AAV transduction while lowering the effective dose or to escape capsid ubiquitination. We will study the effect of AAV mutants and proteasome inhibitors on AAV capsid antigen presentation (Aim 2). It is well-known that the transduction of AAV vectors in mouse models does not always translate into the human. Finally, we will explore the directed evolution approach combined with a rational design strategy to isolate AAV vectors with human hepatocyte specific tropism and the ability to evade a capsid specific CTL response in humanized mice (Aim 3). Elucidation of AAV empty capsid antigen presentation in vivo and the development of an AAV vector with enhanced human liver transduction and CTL immune-evasion will allow us to design safer and more effective strategies that address the current clinical complications for human liver gene therapy using AAV.