Gene therapy for cystic fibrosis: steady progress, should do well.

Abstract

In the early 1990s, when clinical gene therapy trials were initiated for a number of diseases, including cystic fibrosis (CF), there was great expectation both amongst the general public and in some quarters of the scientific and medical profession that this new form of treatment would revolutionize medicine. Recently, a number of articles have been published, with respect to a spectrum of diseases, showing less than encouraging data with regard to such trials [1‐5]. This has been accompanied by a flurry of adverse publicity for gene therapy. The aim of this editorial is to suggest that neither the initial overexpectation, nor the present downturn of opinion, have been justified in considering this new form of treatment. It is well-recognized that a new therapeutic product takes a decade or longer to move from the laboratory to the patient. Gene therapy for CF has had a life span of only half this time, and is already in phase I clinical trials. We would suggest that the pace of progress has, in fact, been exceptional in this field, and it is likely that this will continue to be the case, if not distracted by unreasonable expectations or predictable downturns. Initial studies in vitro [6, 7], and subsequently in animal models in vivo [8, 9], have demonstrated the feasibility of gene therapy for CF. Whilst a number of vector systems are available to allow expression of a normal copy of the cystic fibrosis transmembrane (conductance) regulator (CFTR) gene, two (adenoviruses and cationic liposomes) have received particular attention. At present, only the lungs have been the target of gene therapy trials, which is understandable in the light of the morbidity and mortality related to this organ. Suitable assays to measure the success or otherwise of such gene transfer studies have been developed, focusing both on detection of messenger ribonucleic acid (mRNA) and protein, as well as more specific assays for CFTR function. The former have relied on conventional polymerase chain reaction (PCR) and immunohistochemistry techni-ques. The latter relate to the properties of this protein as a chloride channel in the apical membrane of the respiratory epithelium. This function can be measured both in vivo and in vitro to provide an assay for the efficacy of gene transfer. So far, four phase I clinical trials have been reported in the literature, three using adenovirus [5, 10, 11], and one using cationic liposome [12]. At least a further seven trials are under way or have recently been completed. The adenoviral trials have focused predominantly on the nose but have also included the lung, whilst those using liposomes have so far studied only the nasal epithelium. The reason for the focus on the nose, an organ not predominantly affected in CF, is that it provides easier access both for gene transfer and for measurements, demonstrates the bioelectric abnormality characteristic of the disease, and represents an organ that is likely to be safer for assessment of potential toxicity. The overall picture emerging from these studies is that, in the nasal epithelium, approximately 50% of subjects demonstrate the presence of either mRNA or protein produced as a result of transfer of a normal copy of the CFTR gene. With regard to the important functional endpoints, approximately one third of patients can be shown to demonstrate a degree of correction of the chloride abnormality. With respect to safety, very few problems have been encountered in the nasal epithelium. Importantly, these conclusions are valid both for the adenoviral and liposome-mediated trials, with very similar data. One interim conclusion, therefore, is that in vivo in the nasal epithelium neither system appears to outstrip the other with respect to these characteristics. With regard to the lower airways, the number of patients demonstrating successful gene transfer, as measured by assessment of mRNA or protein, is somewhat less than for the nasal epithelium, the former being around 30%. At the present time, no study has assessed functional correction in the lung because of the lack of a