Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis.
Although first generation recombinant adenoviruses, deleted of sequences spanning E1a and E1b, have been useful for in vivo applications of gene therapy, expression of the recombinant gene has been transient and often associated with the development of inflammation. We show that with first generation adenovirus-mediated gene transfer to the mouse lung, viral proteins are expressed leading to destructive cellular immune responses and repopulation of the lung with nontransgene containing cells. Second generation E1 deleted viruses further crippled by a temperature sensitive mutation in the E2a gene were associated with substantially longer recombinant gene expression and less inflammation. Stable expression of human CF transmembrane conductance regulator has been achieved in lungs of CF mice instilled with a second generation virus.
Yang
Y
Y
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia.
Nunes
F A
FA
Berencsi
K
K
Gönczöl
E
E
Engelhardt
J F
JF
Wilson
J M
JM
D000257:Adenoviridae Infections / Q000821:virology; D017501:Adenovirus E1B Proteins / Q000172:deficiency / Q000235:genetics; D017502:Adenovirus E2 Proteins / Q000172:deficiency / Q000235:genetics*; D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003673:Defective Viruses / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular; D007249:Inflammation; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D011024:Pneumonia, Viral / Q000209:etiology / Q000517:prevention & control / Q000821:virology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D013696:Temperature; D013997:Time Factors
D017501:Adenovirus E1B Proteins; D017502:Adenovirus E2 Proteins; C505032:CFTR protein, human; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator