Gene therapy for the treatment of cystic fibrosis

Figures & data

Table 1 Previous published trials of gene therapy in cystic fibrosis patients

Author	Route of administration	Repeated dose (yes/no)	Safety concerns	Efficacy
				Molecular	PD	Clinical
Viral vectors: adenovirus
1. Zabner et al^Citation35	Nasal	No	No	mRNA-negative	Nasal PD: decrease baseline toward normal values
2. Crystal et al^Citation11	Nasal lung	No	Yes, with highest lung dose	mRNA: some positive in nose, negative in lung	Nasal PD: inconclusive
3. Knowles et al^Citation36	Nasal	No	Mild mucosal inflammation at highest dose		Nasal PD: no change
4. Hay et al^Citation37	Nasal	No	No	CFTR mRNA: some positive	Nasal PD: partial correction Cl^− secretion
5. Zabner et al^Citation9	Nasal	Yes	No		Nasal PD: partial correction of Cl^− secretion; effects reduced with subsequent doses
6. Bellon et al^Citation38	Nasal lung	No	No	mRNA: some positive both routes
7. Harvey et al^Citation39	Lung	Yes	No	mRNA: some positive, decreased with subsequent dose
8. Zuckerman et al^Citation40	Lung	No	Flu-like symptoms at high dose	Vector DNA: positive on Day 4, transient
9. Joseph et al^Citation41 and Perricone et al^Citation42	Lung	No	Mild, nonspecific inflammatory response	mRNA; some positive
Author	Route	Repeated dose (yes/no)	Safety concerns	Efficacy
				mRNA	PD	Clinical
Viral vectors: adeno-associated virus (AAV)
1. Wagner et al^Citation43	Sinus	No	No		Nasal PD: partial correction of Cl^− secretion
2. Aitken et al^Citation44	Lung	No	No	CFTR mRNA: negative
3. Wagner et al^Citation45	Sinus	No	No		Nasal PD: no change	Sinusitis – no change, histology, IL-8: no change L-10: increase
4. Flotte et al^Citation46	Nasal	No	No	CFTR DNA: some positive	No change
5. Moss et al^Citation47	Lung	Yes	No	mRNA negative DNA: some positive		FEV1, IL-8 and IL-10: trend towards improvement.
6. Moss et al^Citation48	Lung	Yes	No			FEV1, sputum markers, requirement for antibiotics: no significant improvement
Non-viral vectors
1. Caplen et al, DC-Chol/DOPE^Citation49	Nasal	No	No	CFTR mRNA: negative	Nasal PD: partial correction of Cl^− secretion
2. Gill et al DC-Chol/DOPE^Citation50	Nasal	No	No		Nasal PD: partial correction Cl^− secretion
3. Porteous et al DOTAP^Citation51	Nasal	No	No	mRNA: some positive	Nasal PD: partial correction Cl^− secretion up to 4 weeks
4. Hyde et al DC-Chol/DOPE^Citation52	Nasal	Yes	No	CFTR mRNA: some positive	Nasal PD: partial Cl^− secretion	CFTR protein: some positive
5. Zabner et al GL67 versus naked pDNA^Citation53	Nasal	No	No		Nasal PD: partial correction of Cl^− secretion; no difference between vectors.
6. Alton et al GL67^Citation54	Nasal lung	No	Flu-like symptoms	mRNA: negative	Bronchial PD: ~25% correction Cl^− secretion	Sputum: IL-8 and neutrophils reduced
7. Ruiz et al (GL67)^Citation55	Lung	No	Flu-like symptoms	CFTR mRNA: 4/8 positive
8. Konstan et al vector: DNA nanoparticles^Citation56	Nasal	No	No	CFTR DNA: positive in all actively treated subjects; cross-contamination in placebo group	Nasal PD: partial to complete Cl^− secretion correction

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2012 American Thoracic Society. Davies JC, Alton EW/Gene therapy for cystic fibrosis/Proceedings of the American Thoracic Society/7/408–414.²⁸ Official Journal of the American Thoracic Society.

Abbreviations: DC-Chol, 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol; DOPE, dioleoylphosphatidylethanolamine; DOTAP, N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate; GL67, Genzyme lipid 67; PD, potential difference.

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CrystalRGMcElvaneyNGRosenfeldMAAdministration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosisNat Gene1994814251

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KnowlesMRHohnekerKWZhouZA controlled study of adenoviral-vector mediated gene transfer in the nasal epithelium of patients with cystic fibrosisN Engl J Med1995333138238317544439

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AitkenMLMossRBWaltzDAA phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung diseaseHum Gene Ther200112151907191611589832

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KonstanMWDavisPBWagenerJSCompacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitutionHum Gene Ther200415121255126915684701

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DaviesJCAltonEWGene therapy for cystic fibrosisProc Am Thorac Soc20107640841421030522

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