Cystic Fibrosis Gene Therapy Clinical Trials

CF gene therapy approaches have been based on the assumption that the target cell population is the respiratory epithelial cells lining the lung, although the majority of clinical trials have used delivery of the GTA to the nasal and maxillary sinus epithelia of CF patient volunteers as a surrogate tissue. In total, there have been 25 published clinical trials for CF and non-viral approaches have accounted for nine of these (Griesenbach & Alton 2009).

The first non-viral clinical trials assessed the safety and efficacy of a single nasal delivery of plasmid DNA containing the CFTR cDNA under the transcriptional control of the SV40 (Caplen et al. 1995) or RSV 3'LTR promoters (Gill et al. 1997) complexed with DC-Chol:DOPE liposomes. Evidence for plasmid DNA transfer, vector-derived CFTR mRNA expression and partial correction of the CFTR Cl- channel defect was obtained in a subset of subjects. Alternative formulations, in which plasmid DNA contained the human CMV immediate early enhancer/promoter, were complexed with DOTAP liposomes (Porteous et al. 1997), EDMPC:Chol liposomes (Noone et al. 2000), or a peptide consisting of the sequence CK30 (Konstan et al. 2004) and were broadly shown to be similarly effective.

Crucially, no important safety considerations were raised after nasal application of any of these formulations. The target cells of the respiratory epithelium are mostly slowly dividing or terminally differentiated, thus ultimately repeated administration of the GTA will be required to treat the chronic lung disease.

The repeated administration of viral vectors appears to be limited by the existence of pre existing neutralising antibodies (Rosenecker et al. 1996), or antibodies produced in response to vector delivery (Halbert et al. 1997). Successful repeat administration of non viral vectors without loss of efficacy has been demonstrated in the human airways after delivery of three doses of plasmid DNA complexed with DC-Chol:DOPE liposomes (Hyde et al. 2000).

Collectively, these clinical studies provided 'proof-of-principle' for CF non viral gene therapy, but highlighted the need for development of formulations with enhanced efficacy.


List of Published CF Gene Therapy Clinical Trials (some of the papers will be publicly available if you follow the PubMed links).


Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial (2007). Moss, R. B. et al., Hum Gene Ther, 18, 726-732.


Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution (2004). Konstan, M. W. et al., Hum Gene Ther, 15, 1255-1269.

Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial (2004). Moss, R. B. et al., Chest, 125, 509-521. Download


Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study (2003). Flotte, T. R. et al., Hum Gene Ther, 14, 1079-1088.


A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies (2002). Wagner, J. A. et al., Hum Gene Ther, 13, 1349-1359.


A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease (2001). Aitken, M. L. et al., Hum Gene Ther, 12, 1907-1916.


Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications (2001). Joseph, P. M. et al., Hum Gene Ther, 12, 1369-1382.

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium (2001). Perricone, M. A. et al., Hum Gene Ther, 12, 1383-1394.

A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis (2001). Ruiz, F. E. et al., Hum Gene Ther, 12, 751-761.


Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis (2000). Hyde, S. C. et al., Gene Ther, 7, 1156-1165. Download

Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis (2000). Noone, P. G. et al., Mol Ther, 1, 105-114. Download


Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial (1999). Alton, E. W. et al., Lancet, 353, 947-954.

Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus (1999). Harvey, B. G. et al., J Clin Invest, 104, 1245-1255.

Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus (1999). Wagner, J. A. et al., Laryngoscope, 109, 266-274.

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). Zuckerman, J. B. et al., Hum Gene Ther, 10, 2973-2985.


Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial (1997). Bellon, G. et al., Hum Gene Ther, 8, 15-25.

A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis (1997). Gill, D. R. et al., Gene Ther, 4, 199-209. Download

Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis (1997). Porteous, D. J. et al., Gene Ther, 4, 210-218. Download

Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo (1997). Zabner, J. et al., J Clin Invest, 100, 1529-1537. Download


Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis (1996). Zabner, J. et al., J Clin Invest, 97, 1504-1511. Download


Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis (1995). Caplen, N. J. et al., Nat Med, 1, 39-46.

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). Hay, J. G. et al., Hum Gene Ther, 6, 1487-1496.

A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis (1995). Knowles, M. R. et al., N Engl J Med, 333, 823-831. Download


Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis (1994). Crystal, R. G. et al., Nat Genet, 8, 42-51.


Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis (1993). Zabner, J. et al., Cell, 75, 207-216.

CF Gene Therapy Clinical Trial Repository

Adenovirus Clinical Trials: 1993-2001 (10)

Zabner, 1993NoseDose-escalation
2e6 – 5e7 pfu
n = 1/dose
NoNo3NPD: decreased baseline towards non-CF values
mRNA: −ve, protein: −ve
Crystal, 1994LungDose-escalation
2e6 - 5e9 pfu
n = 1–2/dose
NoNo4mRNA: − ve
protein: 1/4 + ve
Safety: no vector shedding
At highest dose transient inflammation.
Crystal, 1994NoseDose-escalation
2e5 – 5e7 pfu
n = 2/dose
NoNo4NPD: inconclusive, too variable
mRNA: 1/4 + ve, protein: 1/4 +
Hay, 1995NoseDose-escalation
2e5 – 5e8.5 pfu
n = 1–2/dose
NoNo9NPD: decreased baseline + amiloride towards non-CF values
Partial correction of Cl− transport
Knowles, 1995NoseDose-escalation
2e7 – 5e10 pfu
n = 3/dose
Vehicle control applied on contralat nostril
NoNo12NPD: no change mRNA: 5/12 + ve
Safety: no toxic effects at low doses
At highest dose mild mucosal inflammation 2/3 patients
Zabner, 1996NoseDose-escalation repeat administration 2 doses 2e7 –1e10 pfu
n = 4–6/dose
NoYes6NPD: partial correction of Cl− in some patients, but reduced effect with subsequent administration. All patients developed serum antibodies to vector, but not CFTR
Bellon, 1997NoseDose-escalation
1e5 – 4e8 pfu n = 2/dose
Dose-escalation 1e7 –5.4e8 pfu n = 2/d
NoNo6DNA: 6/6 + ve
mRNA: 4/6 + ve, protein: 4/6 + ve
Expression was transient in nose
Bellon, 1997LungDose-escalation
1e7 – 5.4e8 pfu
n = 2/dose
NoNo6DNA: 1/6 + ve
mRNA: 1/6 + ve, protein: 2/6 + ve
Expression was transient lung
Harvey, 1999LungDose escalation
Repeat administration 3 doses 1e6 – 1e9 pfu
n = 2/dose
NoYes14Sampled 3 and 30 days after each administration mRNA:
1st administration + ve only with highest dose, transient (− ve by day 30)
2nd administration + ve only with intermediate dose, − ve by day 30
3rd administration no expression Anti-Ad neutralising antibodies detected but no close correlation with loss of expression
Zuckerman, 1999LungDose-escalation 2e9 - 2e11 pfu
n = 2–3/dose
NoNo11DNA: + ve on day 4, transient
Immune response: Ad-specific T-cells, mild humoral response
Safety: mild flu-like symptoms observed, resolved about day 10
Joseph, 2001LungDose-escalation
8e6 – 2.5e10 pfu
n = 2–3/dose
NoNo36DNA: 4/5 + ve on day 2
mRNA: 3/5 + ve on day 2
Perricone, 2001LungDose escalation
8e6 - 2.5e10 IU/patient
Lobar instillation or aerosol
No No 14DNA: all + ve on day 2
mRNA: 4/13 + ve on day 2
Expression transient, undetected by day 7. < 3% of airway epithelial cells transfected. Safety: Mild, non-specific inflammatory response (fevers, myalgia). Cleared within 24 h

AAV2 Clinical Trials: 1999-2007 (6)

Wagner, 1999SinusDose-escalation
1 × 102–1 × 105 RU
Single and two doses n = 5/group
NoNo10DNA: 7/10 + ve day 14
DNA: 1/10 + ve day 41
DNA: 1/10 + ve day 70
CFTR mRNA: − ve
NPD: partial Cl− correction in some cases, effect transient
Aitken, 2001LungDose escalation
1e10 – 1e13 DRP n = 3/group
NoNo12DNA: 6/6 + ve up to day 30 with two highest doses
mRNA: − ve
Safety: several adverse effects, three of which possible related to study (pneumonia, exacerbation)
Wagner, 2002Nose1 nostril 1e5 RU
contralateral nostril placebo (n = 23)
NoNo25No change in: rate of sinusitis relapse, NPD, histopathology and IL-8
IL-10: increased vs. placebo at day 90
Flotte, 2003NoseDose-escalation
3e1 RU – 1e9 RU placebo (n = 25) contralateral nostril
NPD: no change
Vector DNA: 2/25 + ve
Moss, 2004LungRepeat admin:
3 doses, 30 days apart 1e13 DRP (n = 37)
YesYes37DNA: 6/6 + ve (only assessed after 3rd dose)
mRNA: − ve
FEV1: trend in improvement day 30
IL-8 and IL-10: sputum IL-8 reduced after 1st dose, IL-10 no change
Safety and immune response: well tolerated, active group developed AAV2-neutralising antibodies
Moss, 2007LungRepeat admin:
3 doses 30 days apart
1e13 DRP
YesYes102No changes in spirometry, days of antibiotic use or induced sputum markers (IL-8 + neutrophil elastase)
Safety: well tolerated

Non-Viral Clinical Trials: 1997-2012 (9)

Caplen, 1995NoseDC-Chol/DOPE
Dose escalation
10–300 µg DNA n = 3/dose
YesNo15 Vector DNA:
7/8 + ve (some problems with false + ves) CFTR mRNA: − ve NPD: partial correction (20%) of Cl− defect towards normal at day 3, undetected by day 7
Safety: well tolerated
Gill, 1997NoseDC-Chol/DOPE/pDNA
40 + 400 μg DNA/nostril
n = 4/dose
YesNo15NPD: 2/8 transient correction of Cl− for 7–15 days
SPQ: 5/8 showed CFTR function
Porteous, 1997NoseDOTAP
400 µg DNA
YesNo16DNA: 7/8 + ve on days 3 and 7
DNA:2/7 + ve on day 28
mRNA: 2/8 + ve on days 3 and 7
NPD: 2/8 partial Cl− correction up to 4 weeks
SPQ: − ve
Zabner, 1997NoseGL67A v naked pDNANoNo12DNA: 8/9 + ve
RNA: − ve, technical problems
NPD: statistically significant correction of Cl− with both GL67 and naked pDNA
No difference between vectors
Alton, 1999Lung & NoseGL67ApDNA
Lung: 42.2 mg DNA
Nose: 11.8 mg DNA
Lipid only placebo
DNA: 8/8 + ve
RNA: − ve
PD: statistically significant Cl− correction in active group, 25% of normal values
SPQ: CFTR function in 5/6 patients
Bacterial adherence: 5/6 patients in active group reduced bacterial binding compared to pre-treatment values
Inflammation: significant reduction of inflammatory cells in sputum in active group similar results (DNA, mRNA, PD, SPQ, bacterial adherence ) in the nose
Safety: 7/8 patients in active group developed flu-like symptoms (fever, headache), resolved within 36 h. 6/8 patients in both groups had mild airway symptoms
Hyde, 2000NoseDC-Chol/DOPE/pDNA
Repeat administration 3 doses 400 μg DNA/nostril
YesYes12DNA: 6/9 + ve after ≥ one dose
DNA: 1/9 + ve for all 3
mRNA: 7/9 + ve after ≥ one dose
mRNA: 1/9 + ve for all 3
Protein: 6/9 + ve after ≥ one dose; 2–15% epithelial cells transfected
NPD: partial Cl− correction in individual patients
SPQ: 5/9 showed CFTR function after ≥ one dose
Bacterial adherence: no difference, but technical problems
Immune responses: no response to CFTR
Importantly, no loss of efficacy with repeated dosing
Noone, 2000NoseEDMPC/pDNA
Dose escalation
0.4–4 mg DNA placebo in contralateral nostril
YesNo 12DNA: all + ve (some cross-contamination to placebo)
mRNA: − ve
NPD: no change
Ruiz, 2001LungGL67A/pDNA
7.9–21.12 mg DNA
NoNo8mRNA: 4/8 + ve, 3/4 received highest dose
Inflammatory response: 4/8 pronounced fever, myalgia within 6 h post-administration. Serum IL-6 increased, but no changes in IL-8, IL-1, TNF-α or IFN-γ. No antibodies to lipid or plasmid
Lipid and DNA have synergistic effect on inflammation
Konstan, 2004NoseDNA Nanoparticles
Dose-escalation 0.8–8.0 mg DNA
n = 2–6/dose contralateral nostril placebo
YesNo12DNA: 12/12 + ve in active but cross-contamination in placebo
NPD: partial to complete Cl− correction 8/12, up to day 6
Safety: well tolerated, no adverse effects related to treatment
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