title: Development of rAAV2-CFTR: History of the First rAAV Vector Product to be Used in Humans.
abstract: The first human gene therapy trials using recombinant adeno-associated virus (rAAV) vectors were performed in cystic fibrosis (CF) patients. Over 100 CF patients were enrolled in 5 separate trials of rAAV2-CFTR administration via nasal, endobronchial, maxillary sinus, and aerosol delivery. Recombinant AAV vectors were designed to deliver the CF transmembrane regulator (CFTR) gene and correct the basic CFTR defect by restoring chloride transport and reverting the upregulation of proinflammatory cytokines. However, vector DNA expression was limited in duration because of the low incidence of integration and natural airway epithelium turnover. In addition, repeated administration of AAV-CFTR vector resulted in a humoral immune response that prevented effective gene transfer from subsequent doses of vector. AAV serotype 2 was used in human trials before the comparison with other serotypes and determination that serotypes 1 and 5 not only possess higher tropism for the airway epithelium, but also are capable of bypassing the binding and trafficking processes-both were important hindrances to the effectiveness of rAAV2. Although rAAV-CFTR gene therapy does not appear likely to supplant newer small-molecule CFTR modulators in the near future, early work with rAAV-CFTR provided an important foundation for later use of rAAV in humans.
authors.affiliation: 1 Horae Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Loring
authors.affiliation: 1 Horae Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|2 Department of Pediatrics, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Mai K
authors.initials: MK
authors.lastname: ElMallah
authors.affiliation: 1 Horae Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|2 Department of Pediatrics, University of Massachusetts Medical School , Worcester, Massachusetts.|3 Microbiology & Physiologic Systems, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D000229:Dependovirus; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020545:Respiratory Mucosa
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator