A Controlled Study of Adenoviral-Vector–Mediated Gene Transfer in the Nasal Epithelium of Patients with Cystic Fibrosis
Michael R. Knowles, M.D., Kathy W. Hohneker, R.N., Zhaoqing Zhou, Ph.D., John C. Olsen, Ph.D., Terry L. Noah, M.D., Ping-Chuan Hu, Ph.D., Margaret W. Leigh, M.D., John F. Engelhardt, Ph.D., Lloyd J. Edwards, Ph.D., Kim R. Jones, M.D., Ph.D., Mariann Grossman, B.S., James M. Wilson, M.D., Ph.D., Larry G. Johnson, M.D., and Richard C. Boucher, M.D.
Background Cystic fibrosis is a monogenic disease that derangesmultiple systems of ion transport in the airways, culminatingin chronic infection and destruction of the lung. The introductionof a normal copy of the cystic fibrosis transmembrane conductanceregulator (CFTR) gene into the airway epithelium through genetransfer is an attractive approach to correcting the underlyingdefects in patients with cystic fibrosis. We tested the feasibilityof gene therapy using adenoviral vectors in the nasal epitheliumof such patients.
Methods An adenoviral vector containing the normal CFTR complementaryDNA in four logarithmically increasing doses (estimated multiplicityof infection, 1, 10, 100, and 1000), or vehicle alone, was administeredin a randomized, blinded fashion to the nasal epithelium of12 patients with cystic fibrosis. Gene transfer was quantitatedby molecular techniques that detected the expression of CFTRmessenger RNA and by functional measurements of transepithelialpotential differences (PDs) to assess abnormalities of ion transportspecific to cystic fibrosis. The safety of this treatment wasmonitored by nasal lavage and biopsy to assess inflammationand vector replication.
Results The adenoviral vector was detected in nasal-lavage fluidby culture, the polymerase chain reaction (PCR), or both ina dose-dependent fashion for up to eight days after vector administration.There was molecular evidence of gene transfer by reverse-transcriptasePCR assays or in situ hybridization in five of six patientstreated at the two highest doses. However, the percentage ofepithelial cells transfected by the vector was very low (<1percent), and measurement of PD across the epithelium revealedno significant restoration of chloride transport or normalizationof sodium transport. At the lower doses of vector, there wereno toxic effects. However, at the highest dose there was mucosalinflammation in two of three patients.
Conclusions In patients with cystic fibrosis, adenoviral-vector–mediatedtransfer of the CFTR gene did not correct functional defectsin nasal epithelium, and local inflammatory responses limitedthe dose of adenovirus that could be administered to overcomethe inefficiency of gene transfer.
Source Information
From the Department of Medicine, Cystic Fibrosis–Pulmonary Research and Treatment Center (M.R.K., K.W.H., Z.Z., J.C.O., K.R.J., L.G.J., R.C.B.), and the Departments of Pediatrics (T.L.N., P.-C.H., M.W.L.) and Biostatistics (L.J.E.), School of Public Health, University of North Carolina, Chapel Hill; and the Institute for Human Gene Therapy and the Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia (J.F.E., M.G., J.M.W.).
Address reprint requests to Dr. Knowles at the Cystic Fibrosis–Pulmonary Research and Treatment Center, 724 Burnett–Womack Bldg., CB 7020, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7020.
Gene Therapy
Alton E., Geddes D. M., Wagner J. A., Knowles M., Boucher R.
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N Engl J Med 1996;
334:332-333, Feb 1, 1996.
Correspondence
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(2003). Replication-Deficient Human Adenovirus Type 35 Vectors for Gene Transfer and Vaccination: Efficient Human Cell Infection and Bypass of Preexisting Adenovirus Immunity. J. Virol.
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[Abstract][Full Text]
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[Abstract][Full Text]
Seiler, M. P., Luner, P., Moninger, T. O., Karp, P. H., Keshavjee, S., Zabner, J.
(2002). Thixotropic Solutions Enhance Viral-Mediated Gene Transfer to Airway Epithelia. Am. J. Respir. Cell Mol. Bio.
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Tibbles, L. A., Spurrell, J. C. L., Bowen, G. P., Liu, Q., Lam, M., Zaiss, A. K., Robbins, S. M., Hollenberg, M. D., Wickham, T. J., Muruve, D. A.
(2002). Activation of p38 and ERK Signaling during Adenovirus Vector Cell Entry Lead to Expression of the C-X-C Chemokine IP-10. J. Virol.
76: 1559-1568
[Abstract][Full Text]
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(2002). Redox Regulation of Adenovirus-Induced AP-1 Activation by Overexpression of Manganese-Containing Superoxide Dismutase. J. Virol.
76: 355-363
[Abstract][Full Text]
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120
: 124S-131S
[Abstract][Full Text]
Isner, J. M., Vale, P. R., Symes, J. F., Losordo, D. W.
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[Abstract][Full Text]
Walters, R. W., van't Hof, W., Yi, S. M. P., Schroth, M. K., Zabner, J., Crystal, R. G., Welsh, M. J.
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75: 7703-7711
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Robinson, C. A., Kuhn, R. J.
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285: 545-550
[Abstract][Full Text]
Jacobs, E. R., Zeldin, D. C.
(2001). The lung HETEs (and EETs) up. Am. J. Physiol. Heart Circ. Physiol.
280: H1-H10
[Abstract][Full Text]
Zsengellér, Z., Otake, K., Hossain, S.-A., Berclaz, P.-Y., Trapnell, B. C.
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74: 9655-9667
[Abstract][Full Text]
Saito, H., Nakamura, H., Kato, S., Inoue, S., Inage, M., Ito, M., Tomoike, H.
(2000). Percutaneous in vivo gene transfer to the peripheral lungs using plasmid-liposome complexes. Am. J. Physiol. Lung Cell. Mol. Physiol.
279: L651-L657
[Abstract][Full Text]
Wioland, M.-A., Fleury–Feith, J., Corlieu, P., Commo, F., Monceaux, G., Lacau-St-Guily, J., Bernaudin, J.-F.
(2000). CFTR, MDR1, and MRP1 Immunolocalization in Normal Human Nasal Respiratory Mucosa. J. Histochem. Cytochem.
48: 1215-1222
[Abstract][Full Text]
Alvarez, R. D., Barnes, M. N., Gomez-Navarro, J., Wang, M., Strong, T. V., Arafat, W., Arani, R. B., Johnson, M. R., Roberts, B. L., Siegal, G. P., Curiel, D. T.
(2000). A Cancer Gene Therapy Approach Utilizing an Anti-erbB-2 Single-Chain Antibody-encoding Adenovirus (AD21): A Phase I Trial. Clin. Cancer Res.
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[Abstract][Full Text]
Orson, F. M., Kinsey, B. M., Hua, P. J., Bhogal, B. S., Densmore, C. L., Barry, M. A.
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164: 6313-6321
[Abstract][Full Text]
Albelda, S. M., Wiewrodt, R., Zuckerman, J. B.
(2000). Gene Therapy for Lung Disease: Hype or Hope?. ANN INTERN MED
132: 649-660
[Abstract][Full Text]
WILSCHANSKI, M., FAMINI, C., BLAU, H., RIVLIN, J., AUGARTEN, A., AVITAL, A., KEREM, B., KEREM, E.
(2000). A Pilot Study of the Effect of Gentamicin on Nasal Potential Difference Measurements in Cystic Fibrosis Patients Carrying Stop Mutations. Am. J. Respir. Crit. Care Med.
161: 860-865
[Abstract][Full Text]
Suda, T., Mora, B. N., D’Ovidio, F., Cooper, J. A., Hiratsuka, M., Zhang, W., Mohanakumar, T., Patterson, G. A.
(2000). IN VIVO ADENOVIRUS-MEDIATED ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE TRANSFER AMELIORATES LUNG ALLOGRAFT ISCHEMIA-REPERFUSION INJURY. J. Thorac. Cardiovasc. Surg.
119: 297-304
[Abstract][Full Text]
Kremer, E. J., Boutin, S., Chillon, M., Danos, O.
(2000). Canine Adenovirus Vectors: an Alternative for Adenovirus-Mediated Gene Transfer. J. Virol.
74: 505-512
[Abstract][Full Text]
GEDDES, D M, ALTON, E W F W
(1999). The CF gene: 10 years on. Thorax
54: 1052-1054
[Full Text]
Nemerow, G. R., Stewart, P. L.
(1999). Role of alpha v Integrins in Adenovirus Cell Entry and Gene Delivery. Microbiol. Mol. Biol. Rev.
63: 725-734
[Abstract][Full Text]
Harvey, B.-G., Hackett, N. R., El-Sawy, T., Rosengart, T. K., Hirschowitz, E. A., Lieberman, M. D., Lesser, M. L., Crystal, R. G.
(1999). Variability of Human Systemic Humoral Immune Responses to Adenovirus Gene Transfer Vectors Administered to Different Organs. J. Virol.
73: 6729-6742
[Abstract][Full Text]
Blackwell, J. L., Miller, C. R., Douglas, J. T., Li, H., Reynolds, P. N., Carroll, W. R., Peters, G. E., Strong, T. V., Curiel, D. T.
(1999). Retargeting to EGFR Enhances Adenovirus Infection Efficiency of Squamous Cell Carcinoma. Arch Otolaryngol Head Neck Surg
125: 856-863
[Abstract][Full Text]
Dow, S. W., Fradkin, L. G., Liggitt, D. H., Willson, A. P., Heath, T. D., Potter, T. A.
(1999). Lipid-DNA Complexes Induce Potent Activation of Innate Immune Responses and Antitumor Activity When Administered Intravenously. J. Immunol.
163: 1552-1561
[Abstract][Full Text]
Look, D. C., Brody, S. L.
(1999). Engineering Viral Vectors to Subvert the Airway Defense Response. Am. J. Respir. Cell Mol. Bio.
20: 1103-1106
[Full Text]
Bogardus, S. T. Jr, Concato, J., Feinstein, A. R.
(1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA
281: 1919-1926
[Abstract][Full Text]
Walters, R. W., Grunst, T., Bergelson, J. M., Finberg, R. W., Welsh, M. J., Zabner, J.
(1999). Basolateral Localization of Fiber Receptors Limits Adenovirus Infection from the Apical Surface of Airway Epithelia. J. Biol. Chem.
274: 10219-10226
[Abstract][Full Text]
Rubin, B. K.
(1999). Emerging Therapies for Cystic Fibrosis Lung Disease. Chest
115: 1120-1126
[Full Text]
Flint, P. W., Shiotani, A., O'Malley, B. W. Jr
(1999). IGF-1 Gene Transfer Into Denervated Rat Laryngeal Muscle. Arch Otolaryngol Head Neck Surg
125: 274-279
[Abstract][Full Text]
Freimuth, P., Springer, K., Berard, C., Hainfeld, J., Bewley, M., Flanagan, J.
(1999). Coxsackievirus and Adenovirus Receptor Amino-Terminal Immunoglobulin V-Related Domain Binds Adenovirus Type 2 and Fiber Knob from Adenovirus Type 12. J. Virol.
73: 1392-1398
[Abstract][Full Text]
Shumaker, H., Amlal, H., Frizzell, R., Ulrich, C. D. II, Soleimani, M.
(1999). CFTR drives Na+-nHCO-3 cotransport in pancreatic duct cells: a basis for defective HCO-3 secretion in CF. Am. J. Physiol. Cell Physiol.
276: C16-C25
[Abstract][Full Text]
GRUBB, B. R., BOUCHER, R. C.
(1999). Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev.
79: 193-214
[Abstract][Full Text]
Wersto, R. P., Rosenthal, E. R., Seth, P. K., Eissa, N. T., Donahue, R. E.
(1998). Recombinant, Replication-Defective Adenovirus Gene Transfer Vectors Induce Cell Cycle Dysregulation and Inappropriate Expression of Cyclin Proteins. J. Virol.
72: 9491-9502
[Abstract][Full Text]
TERAMOTO, S., MATSUSE, T., OKA, T., ITO, H., FUKUCHI, Y., OUCHI, Y.
(1998). Investigation of Effects of Anesthesia and Age on Aspiration in Mice through LacZ Gene Transfer by Recombinant E1-deleted Adenovirus Vectors. Am. J. Respir. Crit. Care Med.
158: 1914-1919
[Abstract][Full Text]
Tuszynski, M. H.
(1998). Review : Gene Therapy: Applications to the Neurosciences and to Neurological Disease. Neuroscientist
4: 398-407
[Abstract]
Teramoto, S., Bartlett, J. S., McCarty, D., Xiao, X., Samulski, R. J., Boucher, R. C.
(1998). Factors Influencing Adeno-Associated Virus-Mediated Gene Transfer to Human Cystic Fibrosis Airway Epithelial Cells: Comparison with Adenovirus Vectors. J. Virol.
72: 8904-8912
[Abstract][Full Text]
Mounkes, L. C., Zhong, W., Cipres-Palacin, G., Heath, T. D., Debs, R. J.
(1998). Proteoglycans Mediate Cationic Liposome-DNA Complex-based Gene Delivery in Vitro and in Vivo. J. Biol. Chem.
273: 26164-26170
[Abstract][Full Text]
CLESHAM, G J
(1998). Gene therapy made difficult. Heart
80: 313-314
[Full Text]
PRADAL, U., CASTELLANI, C., DELMARCO, A., MASTELLA, G.
(1998). Nasal Potential Difference in Congenital Bilateral Absence of the Vas Deferens. Am. J. Respir. Crit. Care Med.
158: 896-901
[Abstract][Full Text]
Gorman, L., Suter, D., Emerick, V., Schumperli, D., Kole, R.
(1998). Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs. Proc. Natl. Acad. Sci. USA
95: 4929-4934
[Abstract][Full Text]
Middleton, P. G, Alton, E. W F W
(1998). Gene therapy for cystic fibrosis: which postman, which box?. Thorax
53: 197-199
[Abstract][Full Text]
Sata, M., Perlman, H., Muruve, D. A., Silver, M., Ikebe, M., Libermann, T. A., Oettgen, P., Walsh, K.
(1998). Fas ligand gene transfer to the vessel wall inhibits neointima formation and overrides the adenovirus-mediated T cell response. Proc. Natl. Acad. Sci. USA
95: 1213-1217
[Abstract][Full Text]
Mohammad-Panah, R., Demolombe, S., Riochet, D., Leblais, V., Loussouarn, G., Pollard, H., Baro, I., Escande, D.
(1998). Hyperexpression of recombinant CFTR in heterologous cells alters its physiological properties. Am. J. Physiol. Cell Physiol.
274: C310-C318
[Abstract][Full Text]
Livingston, J. B., Lu, S., Robinson, H., Anderson, D. J.
(1998). Immunization of the Female Genital Tract with a DNA-Based Vaccine. Infect. Immun.
66: 322-329
[Abstract][Full Text]
Sewell, D. A., Li, D., Duan, L., Westra, W. H., O'Malley, B. W. Jr
(1997). Safety of In Vivo Adenovirus-Mediated Thymidine Kinase Treatment of Oral Cancer. Arch Otolaryngol Head Neck Surg
123: 1298-1302
[Abstract]
Arcasoy, S. M., Latoche, J., Gondor, M., Watkins, S. C., Henderson, R. A., Hughey, R., Finn, O. J., Pilewski, J. M.
(1997). MUC1 and Other Sialoglycoconjugates Inhibit Adenovirus-mediated Gene Transfer to Epithelial Cells. Am. J. Respir. Cell Mol. Bio.
17: 422-435
[Abstract][Full Text]
Manuel, S. M., Guo, Y., Matalon, S.
(1997). Exosurf enhances adenovirus-mediated gene transfer to alveolar type II cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
273: L741-L748
[Abstract][Full Text]
Pearn, J.
(1997). Recent advances: Paediatrics–I: Infancy and early childhood. BMJ
314: 801-801
[Full Text]
Fasbender, A., Zabner, J., Chillon, M., Moninger, T. O., Puga, A. P., Davidson, B. L., Welsh, M. J.
(1997). Complexes of Adenovirus with Polycationic Polymers and Cationic Lipids Increase the Efficiency of Gene Transfer in Vitro and in Vivo. J. Biol. Chem.
272: 6479-6489
[Abstract][Full Text]
Southern, K. W
(1997). Delta F508 in cystic fibrosis: willing but not able. Arch. Dis. Child.
76: 278-282
[Full Text]
Stern, R. C.
(1997). The Diagnosis of Cystic Fibrosis. NEJM
336: 487-491
[Full Text]
Matsui, H., Johnson, L. G., Randell, S. H., Boucher, R. C.
(1997). Loss of Binding and Entry of Liposome-DNA Complexes Decreases Transfection Efficiency in Differentiated Airway Epithelial Cells. J. Biol. Chem.
272: 1117-1126
[Abstract][Full Text]
Ramsey, B. W.
(1996). Management of Pulmonary Disease in Patients with Cystic Fibrosis. NEJM
335: 179-188
[Full Text]
Wilson, J. M.
(1996). Adenoviruses as Gene-Delivery Vehicles. NEJM
334: 1185-1187
[Full Text]
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