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• W3143407781 abstract "We have several points to raise about Larson and colleagues'1Larson JE Morrow SL Happel L Sharp JF Cohen JC Reversal of cystic fibrosis phenotype in mice by gene therapy in utero.Lancet. 1997; 349: 619-620Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar report. First, there seem to be two critical periods during which cftr-/- mice are at greatest risk perinatally,2Snouwaert JN Brigman KK Latour AM et al.An animal model for cystic fibrosis made by gene targeting.Science. 1992; 257: 1083-1088Crossref PubMed Scopus (759) Google Scholar one within the first few days after birth, and a subsequent period at weaning (about 20 days of age). Unfortunately, Larson's report does not tell us the percentage of the CFTR and lac-Z treated mice that survived these initial periods of high mortality. Without this information, we believe that the data are difficult to interpret because adenoviral-mediated gene transfer about 3 days before term will probably produce gene expression for several days after birth. Measurement of chloride transport some 75 days after gene transfer is unlikely to be helpful in assessing whether CFTR function was important in the critical perinatal period. We know of no evidence that gene expression with adenoviral-mediated transfer would have this duration of expression. Thus, we believe that the most likely hypothesis is that CFTR function perinatally during this critical period (rather than in utero) was responsible for the increase in survival.Second, we cannot agree with the statement that the treatment “resulted in a permanent and complete reversal of the lethal cystic fibrosis phenotype”. This lethal phenotype in man relates to the lung, whereas the correction in this case was of a problem seen almost universally in the mice; but, as Larson and colleagues indicate, only in 5–10% of human neonates. Thus, we would not have concluded, as these researchers do, that their findings demonstrate complete reversal of a mammalian lethal genetic disease by somatic gene therapy in vivo.Third, we feel that it is important for the general readership perhaps not involved in gene therapy, to indicate that Larson and colleagues' view that gene therapy trials in human beings “are not successful in replacing CFTR function” is not shared by everyone. The available human data clearly indicate, with either adenoviral or liposome mediated gene transfer, that proof of principle for gene transfer has been achieved. Indeed, in view of the demonstration that low levels of gene transfer may be sufficient to correct the defect3Johnson LG Olsen JC Sarkadi B Moore KL Swanstrom R Boucher RC Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis.Nat Genet. 1992; 2: 21-25Crossref PubMed Scopus (378) Google Scholar, 4Dorin JR Farley R Webb S et al.A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction.Gene Therapy. 1996; 3: 797-801PubMed Google Scholar (probably of relevance in Larson's study in protecting against intestinal disease) we would take the opposite view; gene therapy for cystic fibrosis is making steady and encouraging progress.Last, because of these difficulties, we would not conclude that “permanent replacement of the CFTR-encoded chloride-channel was not required to reverse the disease process”. Although Larson and colleagues' findings are an interesting contribution, they should not be overinterpreted. We do not believe at present that a reassessment of current gene therapy approaches is imperative. We have several points to raise about Larson and colleagues'1Larson JE Morrow SL Happel L Sharp JF Cohen JC Reversal of cystic fibrosis phenotype in mice by gene therapy in utero.Lancet. 1997; 349: 619-620Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar report. First, there seem to be two critical periods during which cftr-/- mice are at greatest risk perinatally,2Snouwaert JN Brigman KK Latour AM et al.An animal model for cystic fibrosis made by gene targeting.Science. 1992; 257: 1083-1088Crossref PubMed Scopus (759) Google Scholar one within the first few days after birth, and a subsequent period at weaning (about 20 days of age). Unfortunately, Larson's report does not tell us the percentage of the CFTR and lac-Z treated mice that survived these initial periods of high mortality. Without this information, we believe that the data are difficult to interpret because adenoviral-mediated gene transfer about 3 days before term will probably produce gene expression for several days after birth. Measurement of chloride transport some 75 days after gene transfer is unlikely to be helpful in assessing whether CFTR function was important in the critical perinatal period. We know of no evidence that gene expression with adenoviral-mediated transfer would have this duration of expression. Thus, we believe that the most likely hypothesis is that CFTR function perinatally during this critical period (rather than in utero) was responsible for the increase in survival. Second, we cannot agree with the statement that the treatment “resulted in a permanent and complete reversal of the lethal cystic fibrosis phenotype”. This lethal phenotype in man relates to the lung, whereas the correction in this case was of a problem seen almost universally in the mice; but, as Larson and colleagues indicate, only in 5–10% of human neonates. Thus, we would not have concluded, as these researchers do, that their findings demonstrate complete reversal of a mammalian lethal genetic disease by somatic gene therapy in vivo. Third, we feel that it is important for the general readership perhaps not involved in gene therapy, to indicate that Larson and colleagues' view that gene therapy trials in human beings “are not successful in replacing CFTR function” is not shared by everyone. The available human data clearly indicate, with either adenoviral or liposome mediated gene transfer, that proof of principle for gene transfer has been achieved. Indeed, in view of the demonstration that low levels of gene transfer may be sufficient to correct the defect3Johnson LG Olsen JC Sarkadi B Moore KL Swanstrom R Boucher RC Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis.Nat Genet. 1992; 2: 21-25Crossref PubMed Scopus (378) Google Scholar, 4Dorin JR Farley R Webb S et al.A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction.Gene Therapy. 1996; 3: 797-801PubMed Google Scholar (probably of relevance in Larson's study in protecting against intestinal disease) we would take the opposite view; gene therapy for cystic fibrosis is making steady and encouraging progress. Last, because of these difficulties, we would not conclude that “permanent replacement of the CFTR-encoded chloride-channel was not required to reverse the disease process”. Although Larson and colleagues' findings are an interesting contribution, they should not be overinterpreted. We do not believe at present that a reassessment of current gene therapy approaches is imperative. Gene therapy for cystic fibrosisAuthor's reply Full-Text PDF" @default.
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• W3143407781 title "Gene therapy for cystic fibrosis" @default.
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