权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Lentiviral Vector-Based Gene Therapy and The Host Genetic Background

基于慢病毒载体的基因治疗和宿主遗传背景

基本信息

批准号：
9302512
负责人：
TAL KAFRI
金额：
$ 75.81万
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：
2015
资助国家：
美国
起止时间：
2015-09-02 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302512
关键词：
Activated Partial Thromboplastin Time measurement Adverse effects Affect Animal Model Animals Antibodies Biological Assay Breeding Candidate Disease Gene Cell Line Cells Cessation of life Clinical Trials Data Development Disease Dose Embryo Enzyme-Linked Immunosorbent Assay Epitopes Factor IX Fibrin fragment D Fibroblasts Firefly Luciferases Future Gene Delivery Gene Expression Genes Genetic Genetic Variation Genome Goals Hepatic Hepatocyte Hereditary Disease Human Human Genetics Image Immune response In Vitro Inbreeding Inheritance Patterns Kinetics Lentivirus Vector Life Cycle Stages Liver Luc Gene Luciferases Maintenance Mediating Modeling Mouse Strains Mus Nuclear Import Oryctolagus cuniculus Outcome Pathology Patients Pattern Pharmaceutical Preparations Phenotype Plasma Process Protocols documentation RNA Recombinants Regimen Resistance Rodent Model Role Safety System T-Lymphocyte Testing Therapeutic Variant Viral Vector Virus Integration aptamer base design expression vector fusion gene gene delivery system gene replacement therapy gene therapy gene therapy clinical trial genetic variant in vivo individual patient integration site knock-down mouse genome mouse model novel outcome forecast outcome prediction overexpression preclinical study preclinical trial promoter public health relevance response screening trait transduction efficiency transgene expression vector vector biodistribution vector genome

项目摘要

DESCRIPTION: In contrast to conventional medications, therapeutic viral vectors are given as a single dose and their levels cannot be adjusted to meet the therapeutic needs of an individual patient. Thus, one cannot overestimate the importance of animal model-based preclinical studies as a means to characterize the efficacy and safety of gene therapy regimens. Most preclinical trials are based on a rodent model comprising a large number of animals of the same strain, and a large animal model involving a smaller number of animals. Importantly, the effects of the genetic background of mouse strains employed in preclinical studies on the safety and efficacy of viral vectors has not been characterized. Similarly the effects of the patient's geneti background on the outcome of gene therapy regimens cannot be evaluated. Consequently, several gene therapy clinical trials have resulted in major adverse effects, which could not be observed in relevant earlier preclinical studies. The overall goal of the proposed studies is to characterize the effects of the host genetic variation on the efficacy and safety of lentiviral vector-based gene replacement therapy. Our experimental approach is premised on the Collaborative Cross (CC) mouse strains, which were derived by a funnel breeding of 8 genetically diverse, inbred founder strains. The genomes of these mouse strains are well defined, and will be utilized to study the overall effects of the host genetic background on the overall efficacy and safety of lentiviral vectors, as well as to identify putative genetic loci affecting these processes, test these variants' effects on the safety and efficiency of transducing human cells, and to evaluate the approach of employing an in vitro strain (potentially patient)-specific mouse embryo fibroblast (MEF's)-based system as a means to predict the safety and efficacy of hepatic gene delivery. In Aim 1, we will focus on characterizing the effects of the hos genetic background on the ability of lentiviral vectors to deliver and maintain long-term hepatic transgene expression, as well as lentiviral vector pattern of integration. F2 intercrosses of CC strains with contrasting phenotypes will be employed to identify genetic loci and the putative candidate genes involved in these processes. The optimal mouse strains for lentiviral vector-based hepatic gene delivery (demonstrating highest long-term transgene expression) will be identified. In Aim 2, we will employ MEF's from the above CC strains to study the effects of the host genetic background on the early steps of, as well as overall lentiviral vector transduction. Gene loci involved in these processes will be identified and their effects on safety and efficacy of vector transduction of human cells will be determined. The ability of the MEF-based model to predict in vivo transduction efficiency will be determined, as will this prediction's efficacy acros genetically diverse strains. In Aim 3, we will characterize the effects of the host genetic background on: the ability of lentiviral vectors to maintain therapeutic levels of factor IX (FIX) n vivo, the immune responses to FIX and vector- transduced hepatocytes, and on the development of thrombotic pathologies in the presence of high levels FIX.