Gene transfer for cystic fibrosis

Ten years ago the cystic fibrosis (CF) gene was cloned. The discovery of the gene encoding the CF transmembrane conductance regulator (CFTR) Cl– channel marked the opening of Chapter 1 in the development of gene transfer as a treatment for this common autosomal recessive disease. One year later, Chapter 1 ended when expression of CFTR in CF epithelial cells corrected the CF Cl– transport defect. From this chapter, we obtained a critical reagent, the CFTR cDNA, and we learned that gene therapy might be feasible. Chapter 2, the initial experiments in gene transfer to people with CF, began in 1993. Since then several studies have administered the CFTR cDNA to humans using adenovirus, adeno-associated virus (AAV), and cationic lipid vectors. The paper by Harvey et al. in this issue of the JCI (1) brings Chapter 2 to a close. Now it is time to ask what have we learned from this paper and from Chapter 2, and where to go from here. Harvey et al (1) sprayed a recombinant adenovirus (E1–, E3–) encoding CFTR onto a small region of bronchial epithelium in people with CF. By using quantitative RT-PCR, they learned that generation of vector-derived transcripts was dose-dependent and, at the highest doses, the normal CFTR transcripts were present at levels >5% of the levels of the endogenous mutated transcripts. 5–10% is significant because that level might be sufficient to have a clinical impact, provided all the cells have a few transcripts or transcripts are present in at least 5–10% of epithelial cells (2, 3). Because of technical limitations, the authors could not address these caveats directly, but their data are not inconsistent with these requirements. Thus, the results are encouraging. In summary, from Chapter 2 we learned that gene transfer to humans with CF works, and gene therapy should work. We now know that CFTR can be expressed in appropriate target tissues, that expression can complement the CF loss of Cl– transport in vivo in humans, and that gene transfer is safe. Thus, there are no theoretical or fundamental problems that absolutely prevent the development of gene therapy. However, we have also learned of some significant barriers and limitations. Two challenges that must be met in the next chapter on gene therapy for CF include limited efficiency of gene transfer and limited persistence of expression. These two issues are related: if the duration of expression could be increased, a lower transduction rate might be acceptable — and, to a lesser extent, the converse.