CF Gene Therapy with adeno-associated viral vectors

使用腺相关病毒载体进行 CF 基因治疗

• 批准号: 9273598
• 负责人: Liudmila Cebotaru
• 金额: $ 66.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273598
• 关键词: Attention; Biodistribution; Capsid; Chickens; Clinical; Clinical Trials; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Disease; Dose; Gene Expression; Gene Transfer; Gene therapy trial; Genes; Genetic; Goals; Health; Human; Immune response; Immunosuppression; Inflammatory Response; Laboratories; Lung; Modeling; Morbidity - disease rate; Mutation; Patients; Primates; Principal Investigator; Proteins; Recombinant adeno-associated virus (rAAV); Recombinants; Reproducibility; Safety; Serine; Serotyping; System; Testing; Therapeutic Agents; Therapeutic Effect; Toxicology; Tyrosine; Viral Vector; Virus; Work; adeno-associated viral vector; base; beta Actin; cystic fibrosis patients; design; experimental study; gene therapy; insight; mortality; mutant; neutralizing antibody; nonhuman primate; novel; novel strategies; novel therapeutics; pre-clinical; programs; promoter; public health relevance; repaired; tat Genes; therapeutic gene; transgene expression; vector

 DESCRIPTION: CF is an autosomal disease that leads to significant morbidity and mortality in patients with the disorder. Experiments conducted by our laboratories led to the first gene therapy trial using AAV vectors. The current proposal is designed to utilize our past expertise to successfully develop a new AAV vector based upon serotype 1 and to utilize this vector in clinical trials in CF patients. Because of the significant benefit that would be derived from the development of new therapies for CF, this application is highly relevant. We have identified three new approaches to overcome challenges to AAV gene therapy for CF: use of AAV1, which is more trophic for the lung; use of 27-264, a truncated version of CFTR that corrects F508 by a novel mechanism; and inclusion of a powerful chicken β-actin (CBA) promoter. The overall goal of this application is to provide the critical next steps in developing AAV1-CFTR as a therapeutic agent. We propose three overall Specific Aims: 1. To evaluate the general safety, toxicology, biodistribution, and immune response to AAV1-27-264- CFTR. 2. To determine whether dosing with an AAV1 vector containing a truncated CFTR will lead to increased expression in a human clinical trial. 3. To assess whether repeat dosing of AAV1-CFTR vectors administered to primates leads to wide- spread gene transfer and CFTR expression. Novelty: This work is novel because it combines the repair of endogenous ΔF508 CFTR by transcomplementation and gene therapies.