***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Gene transfer is an attractive option to treat the basic defect in cystic fibrosis . In a double-blind , placebo-controlled , rising-dose tolerance study in the nasal epithelium , we tested the safety and efficacy of a cationic liposome [ p-ethyl-dimyristoylphosphadityl choline ( EDMPC ) cholesterol ] complexed with an expression plasmid containing hCFTR cDNA .  Eleven adult CF patients were studied in a protocol that allowed comparisons within individual subjects : vector and placebo were sprayed into alternate nostrils at intervals over 7 h. After dosing , vector-specific DNA was present in nasal lavage of all subjects for up to 10 days . There were no adverse events . The vector-treated epithelium did not exhibit a significant increase in CFTR-mediated Cl- conductance from baseline and was not different from the placebo-treated nostril : mean deltaCFTR Cl- conductance , mV + /- SEM , -1.6+/-0.4 vs -0.6+/-0.4 , respectively . CFTR-mediated Cl- conductance increased toward normal during repetitive nasal potential difference measurements over the 3 days before dosing which influenced the postdosing calculations . No vector-specific mRNA was detected in the nasal epithelial scrape biopsies , although endogenous CFTR mRNA was detected in all subjects . We conclude that the lipid-DNA complex is safe , but did not produce consistent evidence of gene transfer to the nasal epithelium by physiologic or molecular measures STUDY OBJECTIVES The primary objective was to determine the safety and tolerability of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator ( CFTR ) complementary DNA ( cDNA ) [ tgAAVCF ] , an adeno-associated virus ( AAV ) vector encoding the complete human CFTR cDNA . Secondary objectives included evaluation of pulmonary function assessed by spirometry , lung abnormalities by high-resolution CT ( H RCT ) , airway cytokines , vector shedding , serum neutralizing antibody to AAV serotype 2 ( AAV2 ) , and gene transfer and expression in a subset of subjects undergoing bronchoscopy with bronchial brushings . DESIGN R and omized , double-blind , placebo-controlled , phase II trial . SETTING Eight cystic fibrosis ( CF ) centers in the United States . SUBJECTS CF patients with mild lung disease , defined as FEV(1 ) > or = 60 % predicted . INTERVENTIONS Subjects were r and omized to inhale three aerosolized doses of 1 x 10(13 ) deoxyribonuclease-resistant particles of tgAAVCF or matching placebo at 30-day intervals using the Pari LC Plus nebulizer ( PARI ; Richmond , VA ) . MEASUREMENTS AND RESULTS Of 42 subjects r and omized , 20 subjects received at least one dose of tgAAVCF and 17 subjects received placebo . No difference in the pattern of adverse events or laboratory abnormalities was noted between the two treatment groups . Improvements in induced-sputum interleukin-8 ( p = 0.03 ) and FEV(1 ) ( p = 0.04 ) were observed at day 14 and day 30 , respectively , in the group receiving tgAAVCF when compared to those receiving placebo . No significant differences in H RCT scans were noted . Vector shedding in sputum was observed at low levels up to 90 days after the third dose of vector . All subjects receiving tgAAVCF exhibited an increase ( by at least fourfold ) in serum AAV2-neutralizing antibodies and detectable levels in BAL fluid from five of six treated subjects undergoing BAL . Gene transfer but not gene expression was detected in a subset of six tgAAVCF subjects who underwent bronchoscopy . CONCLUSIONS Repeat doses of aerosolized tgAAVCF were safe and well tolerated , and result ed in encouraging trends in improvement in pulmonary function in patients with CF and mild lung disease Cationic lipids show promise as vectors for transfer of CFTR cDNA to airway epithelia of patients with cystic fibrosis ( CF ) . However , previous studies have not compared the effect of DNA-lipid to DNA alone . Recently , we developed a formulation of plasmid encoding CFTR ( pCF1-CFTR ) and cationic lipid ( GL-67:DOPE ) that generated greater gene transfer in mouse lung than previously described DNA-lipid vectors . Therefore , we tested the hypothesis that DNA-lipid complexes were more effective than DNA alone at transferring CFTR cDNA to airway epithelia in vivo . We administered complexes of DNA-lipid to one nostril and DNA alone to the other nostril in a r and omized , double-blind study . Electrophysiologic measurements showed that DNA-lipid complexes partially corrected the Cl- transport defect . Importantly , the pCF1-CFTR plasmid alone was at least as effective as complexes of DNA with lipid . Measurements of vector-specific CFTR transcripts also showed gene transfer with both DNA-lipid and DNA alone . These results indicate that nonviral vectors can transfer CFTR cDNA to airway epithelia and at least partially restore the Cl- transport defect characteristic of CF . However , improvements in the overall efficacy of gene transfer are required to develop a treatment for CF 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 Cystic fibrosis ( CF ) , an autosomal recessive disorder result ing from mutations in the cystic fibrosis trans-membrane conductance regulator ( CFTR ) gene , is the most common lethal genetic illness in the Caucasian population . Gene transfer to airway epithelium , using adenoviruses containing normal CFTR cDNA , leads to transient production of CFTR mRNA and , in some studies , to correction of the airway epithelial ion transport defect caused by dysfunctional CFTR . Inflammatory responses to the adenoviral vector have been reported , particularly at high viral titers . We evaluated the effects of adenovirus-mediated CFTR gene transfer to airway epithelium in 36 subjects with CF ( 34 individuals , 2 of whom received two separate doses of vector ) , 20 by lobar instillation and 16 by aerosol administration .  Doses ranged from 8 x 10(6 ) to 2.5 x 10(10 ) infective units ( IU ) , in 0.5-log increments . After lobar administration of low doses there were occasional reports of cough , low- grade temperature , and myalgias . At the highest lobar dose ( 2.5 x 10(9 ) IU ) two of three patients had transient myalgias , fever , and increased sputum production with obvious infiltrates on CT scan . After aerosol administration there were no significant systemic symptoms until the 2.5 x 10(10 ) IU dose , when both patients experienced myalgias and fever that resolved within 24 hr . There were no infiltrates seen on chest CT scans in any of the patients in the aerosol administration group . There were no consistent changes in pulmonary function tests or any significant rise in serum IgG or neutralizing antibodies in patients from either group . Serum , sputum , and nasal cytokines , measured before and after vector administration , showed no correlation with adenoviral dose . Gene transfer to lung cells was inefficient and expression was transient . Cells infected with the vector included mononuclear inflammatory cells as well as cuboidal and columnar epithelial cells . In summary , we found no consistent immune response , no evidence of viral shedding , and no consistent change in pulmonary function in response to adenovirus-mediated CFTR gene transfer . At higher doses there was a mild , nonspecific inflammatory response , as evidence d by fevers and myalgias . Overall , vector administration was tolerated but transfer of CFTR cDNA was inefficient and transgene expression was transient for the doses and method of administration used here The major cause of mortality in patients with cystic fibrosis ( CF ) is lung disease . Expression of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene product in the airways is a potential treatment . Clinical studies in which the CFTR cDNA was delivered to the respiratory epithelia of CF patients have result ed in modest , transient gene expression . It seems likely that repeated administration of the gene transfer vector will be required for long-term gene expression . We have undertaken a double-blinded study in which multiple doses of a DNA/liposome formulation were delivered to the nasal epithelium of CF patients . Ten subjects received plasmid DNA expressing the CFTR cDNA complexed with DC-Chol/DOPE cationic liposomes , whilst two subjects received placebo . Each subject received three doses , administered 4 weeks apart . There was no evidence of inflammation , toxicity or an immune response towards the DNA/liposomes or the expressed CFTR . Nasal epithelial cells were collected 4 days after each dose for a series of efficacy assays including quantitation of vector-specific DNA and mRNA , immunohistochemistry of CFTR protein , bacterial adherence , and detection of halide efflux ex vivo . Airway ion transport was also assessed in vivo by repeated nasal potential difference ( PD ) measurements . On average , six of the treated subjects were positive for CFTR gene transfer after each dose . All subjects positive for CFTR function were also positive for plasmid DNA , plasmid-derived mRNA and CFTR protein . The efficacy measures suggest that unlike high doses of recombinant adenoviral vectors , DNA/liposomes can be successfully re-administered without apparent loss of efficacy Previous studies have demonstrated that delivery of a recombinant adeno-associated virus ( AAV ) vector encoding the complete human cystic fibrosis transmembrane regulator ( CFTR ) cDNA ( tgAAVCF ) to the nose , sinus , and lungs of subjects with cystic fibrosis ( CF ) was safe and well tolerated . In a small r and omized , double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals , encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 ( IL-8 ) levels were seen at early time points . This larger study was conducted to verify these trends . One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis ( forced expiratory flow in 1 sec [FEV1]:60 % predicted ) were r and omized to two aerosolized doses of 1x10(13)DNase-resistant particles of tgAAVCF ( n=51 ) or matching placebo ( n=51 ) administered 30 days apart . Although tgAAVCF was well tolerated , the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo . There were no significant differences in spirometric lung function over time , induced sputum biologic markers , or days of antibiotic use in either treatment group . Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated , but did not result in significant improvement in lung function over time . Because gene transfer is the simplest , most basic way to correct the underlying genetic defect that leads to disease in CF , further research is warranted to develop an effective gene transfer agent for the treatment of CF BACKGROUND We and others have previously reported significant changes in chloride transport after cationic-lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene to the nasal epithelium of patients with cystic fibrosis . We studied the safety and efficacy of this gene transfer to the lungs and nose of patients with cystic fibrosis in a double-blind placebo-controlled trial . METHODS Eight patients with cystic fibrosis were r and omly assigned DNA-lipid complex ( active ) by nebulisation into the lungs followed 1 week later by administration to the nose . Eight control patients followed the same protocol but with the lipid alone ( placebo ) .  Safety was assessed clinical ly , by radiography , by pulmonary function , by induced sputum , and by histological analysis . Efficacy was assessed by analysis of vector-specific CFTR DNA and mRNA , in- 
    Output:
    
There is currently no evidence to support the use of CFTR gene transfer reagents as a treatment for lung disease in people with cystic fibrosis .