Correspondence

Gene Therapy

N Engl J Med 1996; 334:332-333February 1, 1996

Article

To the Editor:

The report by Knowles et al. (Sept. 28 issue)1 and the accompanying editorial2 on gene therapy for cystic fibrosis gave a very fair account of some of the difficulties involved. We are concerned, however, that the two articles taken together may send an unbalanced message. A study of liposome-based gene therapy reported recently,3 with a trial design very similar to that of Knowles et al., gave encouraging results — a correction of the chloride-permeability defect of approximately 20 percent without any adverse effects. Although this is unlikely to be adequate for therapy, the understanding of liposome-mediated gene transfer is advancing rapidly. We would therefore question whether the future lies only in either immunosuppression to limit viral side effects or the development of improved viral vectors as suggested, rather than also in the development of more efficient nonviral vectors.

We now know that both adenoviral-mediated and liposome-mediated transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene into human airway epithelium in vivo is an inefficient process. Although these reports are valuable and correct some of the overenthusiasm surrounding gene therapy, it would be a great pity if they pushed the pendulum too far the other way by ignoring the possibilities for nonviral delivery systems for gene therapy.

Eric Alton, M.D.
Duncan M. Geddes, M.D.
Imperial College of Science, Technology and Medicine, London SW3 6LR, United Kingdom

3 References

1
Knowles MR, Hohneker KW, Zhou Z, et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N Engl J Med 1995;333:823-831
Full Text | Web of Science | Medline

2
Leiden JM. Gene therapy -- promise, pitfalls, and prognosis. N Engl J Med 1995;333:871-873
Full Text | Web of Science | Medline

3
Caplen NJ, Alton EWFW, Middleton PG, et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1995;1:39-46
CrossRef | Web of Science | Medline

To the Editor:

Knowles et al. provided an excellent and long-overdue randomized, double-blind appraisal of the prospects for gene therapy that uses a first-generation adenoviral vector capable of transducing the CFTR gene. Their observation that local inflammatory responses probably blocked the correction of chloride transport by the adenoviral vector surprised few researchers in the field. In fact, inflammation secondary to first-generation adenoviral vectors is thought to be a major limitation of these vectors.1,2

However, the media reaction to this Journal article was surprising. Many newspapers and news magazines published stories claiming, for example, that “scientists may have pushed too far too fast in a race for [gene therapy] breakthroughs,”3 and that “five years of [gene therapy] attempts have cured no one.”4 The hyperbole can be traced back to the media, not to participating scientists.

The vast majority of approved clinical trials of gene therapy are focused on the safety, not the efficacy, of this new technology. The continued focus on safety conflicts with the rush to develop this technology and partially explains the fact that gene therapy has yet to cure patients. Furthermore, the complex and highly regulated approval process for gene-therapy protocols, involving multiple reviews by local institutions as well as reviews by the Food and Drug Administration and the Recombinant DNA advisory Committee of the National Institutes of Health, prohibits an excessive or premature rush to the marketplace for gene therapy. Instead, current gene-therapy research, such as the observations of Knowles et al., sets the stage for future research — a process integral to the scientific method. Many developments are already in progress for gene therapy of cystic fibrosis with the use of new second-generation adenoviral vectors, adeno-associated viral vectors, and liposomal gene transfer.2 The promises of gene therapy will probably be fulfilled, but patients and the public must understand that the process is hard work and may take a long time.

John A. Wagner, M.D., Ph.D.
Stanford University Medical Center, Stanford, CA 94305-5332

4 References

1
Crystal RG, McElvaney NG, Rosenfeld MA, et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 1994;8:42-51
CrossRef | Web of Science | Medline

2
Wagner JA, Chao AC, Gardner P. Molecular strategies for therapy of cystic fibrosis. Annu Rev Pharmacol Toxicol 1995;35:257-276
CrossRef | Web of Science | Medline

3
Bjerklie D, Park A. Has gene therapy stalled? Time. October 9, 1995:62-3.

4
Begley S, Murr A, Hager M. Promises, promises. Newsweek. October 9, 1995:60-2.

Author/Editor Response

The authors reply:

To the Editor: We remain enthusiastic about gene therapy, despite the slower-than-hoped-for rate of progress and the inefficiency of current adenoviral-mediated and liposomal-mediated CFTR gene transfer.1,2 One of the intents of our paper was to alert researchers in the field to problems with the efficiency of the adenovirus and consequently to stimulate new approaches to increase the efficiency of this vector by the use of other serotypes or new dosing strategies. Liposomes are also less efficient than we would like, as evidenced by the fact that the “encouraging results” of the study by Caplen et al.2 that Drs. Alton and Geddes mention were modest and transient (lasting a few days) and required repetitive dosing (every 10 to 15 minutes) for up to 7 hours. We agree with Drs. Alton and Geddes that we should continue a broad-based approach to the development of vectors, including liposomes, as emphasized in the last paragraph of our report. As Dr. Wagner indicates, progress will result from iterative basic-science and clinical-research studies. Our study revealed low-level gene transfer and illustrates how quantitative this field has become. Such is the expected course of events in a new area of applied biology, as addressed in the editorial by Dr. Leiden,3 and we remain optimistic that continued efforts will yield benefits for the application of gene therapy to the treatment of human disease.

Michael Knowles, M.D.
Richard Boucher, M.D.
University of North Carolina, Chapel Hill, NC 27599-7020

3 References

1
Crystal RG, McElvaney NG, Rosenfeld MA, et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 1994;8:42-51
CrossRef | Web of Science | Medline

2
Caplen NJ, Alton EWFW, Middleton PG, et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1995;1:39-46
CrossRef | Web of Science | Medline