Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus.

We sought to evaluate the ability of an E1(-), E3(-) adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 10(6) to 2 x 10(9) plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose-dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

[1]  Loyd,et al.  A CONTROLLED STUDY OF ADENOVIRAL-VECTOR–MEDIATED GENE TRANSFER IN THE NASAL EPITHELIUM OF PATIENTS WITH CYSTIC FIBROSIS , 2000 .

[2]  K. Propert,et al.  A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis. , 1999, Human gene therapy.

[3]  N. Hackett,et al.  Variability of Human Systemic Humoral Immune Responses to Adenovirus Gene Transfer Vectors Administered to Different Organs , 1999, Journal of Virology.

[4]  K. Elkon,et al.  Inhibition of Tumor Necrosis Factor Alpha by an Adenovirus-Encoded Soluble Fusion Protein Extends Transgene Expression in the Liver and Lung , 1999, Journal of Virology.

[5]  M. Welsh,et al.  Basolateral Localization of Fiber Receptors Limits Adenovirus Infection from the Apical Surface of Airway Epithelia* , 1999, The Journal of Biological Chemistry.

[6]  J. Zabner,et al.  Delivery of an adenovirus vector in a calcium phosphate coprecipitate enhances the therapeutic index of gene transfer to airway epithelia. , 1999, Human gene therapy.

[7]  C. Miller,et al.  An Adenovirus Vector with Genetically Modified Fibers Demonstrates Expanded Tropism via Utilization of a Coxsackievirus and Adenovirus Receptor-Independent Cell Entry Mechanism , 1998, Journal of Virology.

[8]  B. Trapnell,et al.  Lung-specific expression of adenovirus E3-14.7K in transgenic mice attenuates adenoviral vector-mediated lung inflammation and enhances transgene expression. , 1998, Human gene therapy.

[9]  S. Randell,et al.  Limited Entry of Adenovirus Vectors into Well-Differentiated Airway Epithelium Is Responsible for Inefficient Gene Transfer , 1998, Journal of Virology.

[10]  T. Flotte,et al.  Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus , 1998, The Lancet.

[11]  L. Turka,et al.  Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig , 1998, Gene Therapy.

[12]  T. Flotte,et al.  Adeno-associated virus vectors for gene therapy of cystic fibrosis. , 1998, Methods in enzymology.

[13]  J. Wilson,et al.  Lentiviral vectors for gene therapy of cystic fibrosis. , 1997, Human gene therapy.

[14]  B. Tümmler,et al.  Decreased expression of the cystic fibrosis transmembrane conductance regulator protein in remodeled airway epithelium from lung transplanted patients. , 1997, Human pathology.

[15]  A. Amalfitano,et al.  Isolation and characterization of packaging cell lines that coexpress the adenovirus E1, DNA polymerase, and preterminal proteins: implications for gene therapy , 1997, Gene Therapy.

[16]  D. Gill,et al.  A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis , 1997, Gene Therapy.

[17]  G. Mclachlan,et al.  Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis , 1997, Gene Therapy.

[18]  Alan E. Smith,et al.  Effect of the E4 region on the persistence of transgene expression from adenovirus vectors , 1997, Journal of virology.

[19]  C. Langston,et al.  Exogenous surfactant enhances the delivery of recombinant adenoviral vectors to the lung. , 1997, Human gene therapy.

[20]  R. Crystal,et al.  Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. , 1997, Human gene therapy.

[21]  G. Bellon,et al.  Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. , 1997, Human gene therapy.

[22]  P. A. Peterson,et al.  Characterization of factors involved in modulating persistence of transgene expression from recombinant adenovirus in the mouse lung. , 1997, Human gene therapy.

[23]  D. Brough,et al.  Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types , 1996, Nature Biotechnology.

[24]  D. Porteous,et al.  A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction. , 1996, Gene therapy.

[25]  L. Kunkel,et al.  A method to codetect introduced genes and their products in gene therapy protocols , 1996, Nature Biotechnology.

[26]  J. Wilson,et al.  Adenoviruses as gene-delivery vehicles. , 1996, The New England journal of medicine.

[27]  R. Gibson,et al.  Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. , 1996, The Journal of clinical investigation.

[28]  R. Crystal,et al.  Quantitative assessment of the epithelial and inflammatory cell populations in large airways of normals and individuals with cystic fibrosis. , 1996, American journal of respiratory and critical care medicine.

[29]  B. Harvey,et al.  "Sero-switch" adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. , 1996, Human gene therapy.

[30]  R. Crystal,et al.  Modification of nasal epithelial potential differences of individuals with cystic fibrosis consequent to local administration of a normal CFTR cDNA adenovirus gene transfer vector. , 1995, Human gene therapy.

[31]  H. Ertl,et al.  Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses , 1995, Journal of virology.

[32]  R. Crystal,et al.  Modulation of gene expression after replication-deficient, recombinant adenovirus-mediated gene transfer by the product of a second adenovirus vector. , 1995, Gene therapy.

[33]  R. Crystal,et al.  IL-6 release and airway administration of human CFTR cDNA adenovirus vector , 1995, Nature Medicine.

[34]  James M. Wilson,et al.  Gene therapy in a xenograft model of cystic fibrosis lung corrects chloride transport more effectively than the sodium defect , 1995, Nature Genetics.

[35]  A. Tosteson,et al.  Changes in dyspnea, health status, and lung function in chronic airway disease. , 1995, American journal of respiratory and critical care medicine.

[36]  S. Durham,et al.  Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis , 1995, Nature Medicine.

[37]  James M. Wilson,et al.  Prolonged transgene expression in cotton rat lung with recombinant adenoviruses defective in E2a. , 1994, Human gene therapy.

[38]  R. Crystal,et al.  Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis , 1994, Nature Genetics.

[39]  Joseph Zabner,et al.  Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis , 1993, Cell.

[40]  R. Crystal,et al.  Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis. , 1992, The Journal of clinical investigation.

[41]  M. Perricaudet,et al.  In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium , 1992, Cell.

[42]  J C Olsen,et al.  Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis , 1992, Nature genetics.

[43]  R. Crystal,et al.  Expression of the cystic fibrosis transmembrane conductance regulator gene in cells of non-epithelial origin. , 1991, Nucleic acids research.

[44]  V. Ferrans,et al.  Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Moss,et al.  Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium. , 1991, The EMBO journal.

[46]  L. Tsui,et al.  Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. , 1990, The New England journal of medicine.

[47]  M. Hodson,et al.  Identification of the cystic fibrosis gene. , 1990, BMJ.

[48]  M. V. Doyle,et al.  Quantitation of mRNA by the polymerase chain reaction. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[49]  L. Tsui,et al.  Erratum: Identification of the Cystic Fibrosis Gene: Genetic Analysis , 1989, Science.

[50]  J. Riordan,et al.  Identification of the Cystic Fibrosis Gene : Chromosome Walking and Jumping Author ( s ) : , 2008 .

[51]  L. Tsui,et al.  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. , 1989, Science.

[52]  L. Tsui,et al.  Identification of the cystic fibrosis gene: genetic analysis. , 1989, Science.

[53]  P. Quinton.  Missing Cl conductance in cystic fibrosis. , 1986, The American journal of physiology.