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Development of AAV vectors for CF therapy

用于 CF 治疗的 AAV 载体的开发

基本信息

批准号：
10544549
负责人：
Chengwen Li
金额：
$ 38.88万
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：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544549
关键词：
Address Airway Disease Animal Model Binding Blindness Blood Blood Coagulation Disorders Blood Vessels CRISPR/Cas technology Capsid Clinical Trials Complication Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Dependovirus Development Directed Molecular Evolution Disease Epithelial Cells Failure Gene Delivery Genes Genetic Diseases Genetic Engineering Genome Hemorrhage High Prevalence Human In Vitro Incubated Intravenous Immunoglobulins Libraries Longitudinal Studies Lung Lung diseases Measurable Mediating Morbidity - disease rate Mus Mutation Organ Patients Peptides Peripheral Persons Phage Display Phenotype Property Proteins Regulator Genes Serotyping Technology Testing Tissues Transduction Gene Variant Vascular Permeabilities Viral Genome Viral Packaging Virion adeno-associated viral vector airway epithelium apical membrane autosome basolateral membrane cellular transduction cystic fibrosis airway epithelia cystic fibrosis mouse cystic fibrosis patients delivery vehicle ds-DNA early phase clinical trial gene therapy improved mortality mutant neutralizing antibody novel novel strategies pulmonary function recessive genetic trait small molecule success transduction efficiency vector vector induced

项目摘要

Abstract Cystic fibrosis (CF) is caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. Airway disease is the leading cause of morbidity and mortality. Gene therapy offers a potential cure for CF. Among gene delivery vehicles, adeno-associated virus (AAV) vectors have demonstrated success in clinical trials. AAV vectors have also been tested in CF patients via airway delivery for gene addition but without measurable success perhaps due to physical airway barriers and inefficient transduction. Studies have shown that higher AAV transduction of airway epithelial cells occur via the basolateral membrane in vitro and our preliminary study demonstrated that systemic administration of AAV vectors induced much more efficient lung transduction than airway delivery in mice. These findings strongly suggest that AAV can transduce airway epithelial cells via systemic administration. The efficiency of AAV transduction in airway epithelial cells after systemic delivery of AAV vectors is usually restricted by the blood vascular barrier and a high prevalence of AAV neutralizing antibodies (Nabs). In this proposal, based on our previous studies, we will explore different strategies to develop novel AAV vectors using directed evolution and AAV virion specific binding peptides via phage display technology to increase AAV vector vascular permeability for enhanced transduction in airway epithelial cells and to evade Nabs after systemic administration. Finally, the novel approaches developed in this proposal will be used to deliver optimized CRISPR/Cas9 specific for CFTR del508 to CF mice and study the long-term phenotypic correction. The results generated from these studies will allow us to develop an effective approach to treat CF patients using AAV vector mediated gene delivery. .

摘要