CF Gene Therapy with adeno-associated viral vectors

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 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.