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A step towards gene therapy for CF
MOLECULAR MEDICINE TODAY, JULY 1999 (VOL. 5)
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A step towards gene therapy for CF had decreased bacterial binding to lung The first safe and effective partial correction tissue after being treated. As these of the genetic defect in cystic fibrosis (CF) pathogens are responsible for a large has been recently reported by researchers proportion of CF-related severe lung from the UK. CF is caused by a defect in the disease, any treatment that shows reduction cystic fibrosis transmembrane conductance in their adherence is potentially of great regulator (CFTR) gene, which encodes a clinical interest. Future Phase II/III trials cAMP-regulated chloride channel. If the will measure clinical features and qualitygene is defective, chloride transport on the of-life parameters, such as frequency of apical surface of epithelial cells is impaired antibiotic use and hospitalizations. and absorption of sodium ions increases. By The only side effects in the trial were transferring a normal CFTR gene to the influenza-like symptoms that occurred in lungs and noses of CF patients, Eric Alton the patients who received the gene. As (Imperial College, London, UK) and these symptoms could be easily relieved, colleagues have partially corrected chloride Alton considers them to be minor. abnormalities in these tissues and have However, as the lungs of CF patients are reduced bacterial adherence to CF lung Figure 1. A cystic fibrosis patient receiving intranasal gene chronically inflamed, even minor irritation tissue1. therapy. Picture kindly provided by Dr Eric Alton, Imperial might be exacerbated by repeated The life expectancy of a CF individual is College School of Medicine at the National Heart and Lung administration, and it is not yet clear how ~30 years, and lung disease is the main Institute, London, UK. often treatment should be given. Gene cause of morbidity and mortality. As it is a expression in the nasal mucosa was seen single-gene defect, affecting ~1:2000 for up to three weeks. Caucasians, it is a lead target for Changes in chloride efflux were assessed in the As it is difficult for therapeutic agents to experimental gene therapy. study by using novel in vivo electrophysiological penetrate the abnormal mucus in the lungs of CF Soon after the discovery of CFTR (Ref. 2), the assays to record lower-airway and nasal potential patients, clinical studies will, in the future, focus gene was transferred successfully to the nasal differences. The responses to low chloride and the on ways to remove or change this mucus by using mucosa of transgenic ‘CF’ laboratory mice. The cAMP agonist, isoprenaline, in the treatment mucolytic agents. A long-term approach might be first clinical trials of CFTR gene transfer also group showed that the gene could restore ~20% of to treat patients in childhood as the lungs of CF targeted the nasal mucosa, but whereas groups in the normal chloride efflux in the nasal epithelia patients are normal at birth. However, it will be the USA and France used adenovirus vectors, and ~25% in the lung epithelia. The correction in essential to prove safety and efficacy in adults researchers in the UK used cationic liposomes to before this approach can be taken. The main deliver the gene. Cationic liposomes are positively the lung was an exciting finding, as Alton explains: ‘This is the first demonstration that gene barrier to clinical progress remains the charged lipids that form complexes with transfer can correct the chloride defect in the effectiveness of the delivery system. As Alton negatively charged DNA. Because they mix with target organ: the lungs of cystic fibrosis patients.’ says, ‘Increasing gene transfer efficiency is still cell membranes, they allow DNA that encodes the The clinical effectiveness of improving only the the key issue.’ normal CFTR gene to be incorporated into cells. chloride defect is not yet known, and as a higher Up to 25% of the chloride defect can now be proportion of non-CF cells is needed to correct the 1 Alton, E.W.F. et al. (1999) Cationic lipidcorrected in the nasal mucosa of CF patients by defect in sodium transport, its correction was not either delivery method3 (see Fig. 1), although the mediated CFTR gene transfer to the lungs adenovirus vector produced adverse side effects in seen in this trial. It is also not clear which and nose of patients with cystic fibrosis: a epithelial cell type should be targeted. some of the CF patients treated this way4. double-blind placebo-controlled study, Alton’s group observed a clear correlation in In this study, Alton and colleagues performed a Lancet 353, 947–954 electrochemical measurements between the lung Phase I, double-blind, placebo-controlled clinical 2 Kerem, B. et al. (1989) Identification of the and nasal tissues. However, there was a lower trial in which 16 male CF patients were divided cystic fibrosis gene: genetic analysis, Science correlation between results in the two tissue types into two groups. Those in the treatment group 245, 1073–1080 in some safety-related assays. This underlines the received a single dose of the CFTR gene in a 3 Davies, J.C. et al. (1998) Prospects for gene fact that the nose, which is the easier tissue to complex with the cationic lipid, GLtherapy for cystic fibrosis, Mol. Med. Today 4, treat, is not a perfect model for the lung. 67/DOPE/DMPE-PEG5000, whereas those in the 292–299 Because the lungs of adults and older children placebo group received only the lipid. This study 4 Knowles, M.R. et al. (1995) A controlled study with CF are infected by the pathogens was designed to assess the safety and efficacy of of adenoviral-vector-mediated gene transfer Pseudomonas aeruginosa and Burkholderia CFTR gene delivery. As Alton explains, ‘This in the nasal epithelium of patients with cystic cepacia, Alton and colleagues measured the single-dose study was designed to test the fibrosis, New Engl. J. Med. 333, 823–831 changes in P. aeruginosa adhesion to lung principle of correcting the basic defect and epithelial cells by scanning electron microscopy. assessing safety. It could not prove clinical Clare Sansom Five of the eight patients in the treatment group effectiveness.’ Freelance science writer
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.
279
N
e
w
s
A step towards gene therapy for CF had decreased bacterial binding to lung The first safe and effective partial correction tissue after being treated. As these of the genetic defect in cystic fibrosis (CF) pathogens are responsible for a large has been recently reported by researchers proportion of CF-related severe lung from the UK. CF is caused by a defect in the disease, any treatment that shows reduction cystic fibrosis transmembrane conductance in their adherence is potentially of great regulator (CFTR) gene, which encodes a clinical interest. Future Phase II/III trials cAMP-regulated chloride channel. If the will measure clinical features and qualitygene is defective, chloride transport on the of-life parameters, such as frequency of apical surface of epithelial cells is impaired antibiotic use and hospitalizations. and absorption of sodium ions increases. By The only side effects in the trial were transferring a normal CFTR gene to the influenza-like symptoms that occurred in lungs and noses of CF patients, Eric Alton the patients who received the gene. As (Imperial College, London, UK) and these symptoms could be easily relieved, colleagues have partially corrected chloride Alton considers them to be minor. abnormalities in these tissues and have However, as the lungs of CF patients are reduced bacterial adherence to CF lung Figure 1. A cystic fibrosis patient receiving intranasal gene chronically inflamed, even minor irritation tissue1. therapy. Picture kindly provided by Dr Eric Alton, Imperial might be exacerbated by repeated The life expectancy of a CF individual is College School of Medicine at the National Heart and Lung administration, and it is not yet clear how ~30 years, and lung disease is the main Institute, London, UK. often treatment should be given. Gene cause of morbidity and mortality. As it is a expression in the nasal mucosa was seen single-gene defect, affecting ~1:2000 for up to three weeks. Caucasians, it is a lead target for Changes in chloride efflux were assessed in the As it is difficult for therapeutic agents to experimental gene therapy. study by using novel in vivo electrophysiological penetrate the abnormal mucus in the lungs of CF Soon after the discovery of CFTR (Ref. 2), the assays to record lower-airway and nasal potential patients, clinical studies will, in the future, focus gene was transferred successfully to the nasal differences. The responses to low chloride and the on ways to remove or change this mucus by using mucosa of transgenic ‘CF’ laboratory mice. The cAMP agonist, isoprenaline, in the treatment mucolytic agents. A long-term approach might be first clinical trials of CFTR gene transfer also group showed that the gene could restore ~20% of to treat patients in childhood as the lungs of CF targeted the nasal mucosa, but whereas groups in the normal chloride efflux in the nasal epithelia patients are normal at birth. However, it will be the USA and France used adenovirus vectors, and ~25% in the lung epithelia. The correction in essential to prove safety and efficacy in adults researchers in the UK used cationic liposomes to before this approach can be taken. The main deliver the gene. Cationic liposomes are positively the lung was an exciting finding, as Alton explains: ‘This is the first demonstration that gene barrier to clinical progress remains the charged lipids that form complexes with transfer can correct the chloride defect in the effectiveness of the delivery system. As Alton negatively charged DNA. Because they mix with target organ: the lungs of cystic fibrosis patients.’ says, ‘Increasing gene transfer efficiency is still cell membranes, they allow DNA that encodes the The clinical effectiveness of improving only the the key issue.’ normal CFTR gene to be incorporated into cells. chloride defect is not yet known, and as a higher Up to 25% of the chloride defect can now be proportion of non-CF cells is needed to correct the 1 Alton, E.W.F. et al. (1999) Cationic lipidcorrected in the nasal mucosa of CF patients by defect in sodium transport, its correction was not either delivery method3 (see Fig. 1), although the mediated CFTR gene transfer to the lungs adenovirus vector produced adverse side effects in seen in this trial. It is also not clear which and nose of patients with cystic fibrosis: a epithelial cell type should be targeted. some of the CF patients treated this way4. double-blind placebo-controlled study, Alton’s group observed a clear correlation in In this study, Alton and colleagues performed a Lancet 353, 947–954 electrochemical measurements between the lung Phase I, double-blind, placebo-controlled clinical 2 Kerem, B. et al. (1989) Identification of the and nasal tissues. However, there was a lower trial in which 16 male CF patients were divided cystic fibrosis gene: genetic analysis, Science correlation between results in the two tissue types into two groups. Those in the treatment group 245, 1073–1080 in some safety-related assays. This underlines the received a single dose of the CFTR gene in a 3 Davies, J.C. et al. (1998) Prospects for gene fact that the nose, which is the easier tissue to complex with the cationic lipid, GLtherapy for cystic fibrosis, Mol. Med. Today 4, treat, is not a perfect model for the lung. 67/DOPE/DMPE-PEG5000, whereas those in the 292–299 Because the lungs of adults and older children placebo group received only the lipid. This study 4 Knowles, M.R. et al. (1995) A controlled study with CF are infected by the pathogens was designed to assess the safety and efficacy of of adenoviral-vector-mediated gene transfer Pseudomonas aeruginosa and Burkholderia CFTR gene delivery. As Alton explains, ‘This in the nasal epithelium of patients with cystic cepacia, Alton and colleagues measured the single-dose study was designed to test the fibrosis, New Engl. J. Med. 333, 823–831 changes in P. aeruginosa adhesion to lung principle of correcting the basic defect and epithelial cells by scanning electron microscopy. assessing safety. It could not prove clinical Clare Sansom Five of the eight patients in the treatment group effectiveness.’ Freelance science writer
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.
279