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 ?-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 ?F508 CFTR by transcomplementation and gene therapies.

Public Health Relevance

CF is an autosomal recessive disorder causing significant health problems. There are over 1000 mutations. The ultimate goal is to develop a gene therapy for CFTR based on adenoassociated viral vectors, which would ultimately help the majority of CF patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Lachowicz-Scroggins, Marrah Elizabeth
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Bergbower, Emily; Boinot, Clement; Sabirzhanova, Inna et al. (2018) The CFTR-Associated Ligand Arrests the Trafficking of the Mutant ?F508 CFTR Channel in the ER Contributing to Cystic Fibrosis. Cell Physiol Biochem 45:639-655
Guggino, William B; Cebotaru, Liudmila (2017) Adeno-Associated Virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments. Expert Opin Biol Ther 17:1265-1273
Guggino, William B; Benson, Janet; Seagrave, JeanClare et al. (2017) A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System. Hum Gene Ther Clin Dev 28:145-156