ABSTRACT
Therapy for CF continues to be aimed at the treatment of symptoms.2 The identification of the CFTR gene raised the possibility that therapies could be devised to ameliorate or circumvent the disease process at the molecular level. Indeed, a number of approaches appeared feasible based upon in vitro or animal studies but have not proven to be efficacious at the clinical level. One example is the use of agonists of the adenylate cyclase/protein kinase A pathway to increase the activity of mutant CFTR.162,163 Despite impressive effects in CF airway cell lines and nasal epithelium of CF mice, humans with CF did not generate appreciable chloride secretion in response to these agents.164,165 One of the hurdles faced by molecular based therapy is the need to tailor treatment to the specific defect. Thus, misfolding of CFTR caused by the F508 mutation may require a different approach than loss of CFTR synthesis due to a nonsense mutation.166 Mutationspecific therapies are currently under development.167,168
Correction of the CFTR defect by providing a working copy of the protein has been an attractive yet elusive goal. Gene therapy using a variety of vectors, both viral and nonviral, has been extensively investigated for applications in CF.169 Currently, the adeno-associated virus (AAV) has the most favorable attributes for gene transfer to pulmonary epithelia. While AAV appears safe, efficacy of gene expression is suboptimal.170-172 Although the concept of gene replacement remains sound in principle, a number of technical and biological hurdles remain.173 Eventually, correction of endogenous CFTR genes using short DNA sequences transferred to lung epithelia by nonbiologic vectors, may provide the highest safety and greatest efficacy.174
