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Cystic fibrosis: Investigational therapies

Richard H Simon, MD
Thomas H Sisson, MD
Section Editor
George B Mallory, MD
Deputy Editor
Alison G Hoppin, MD


The survival rate of patients with cystic fibrosis (CF) continues to improve. In 1985, the median predicted survival was 25 years of age, while in 2011 it had increased to 41 years [1]. In an effort to further prolong the life span of patients with CF, many potential new treatments are being actively investigated. This topic review will summarize some of the experimental therapies whose development has advanced to clinical trials in patients with CF. They include approaches to replace the abnormal CF transmembrane conductance regulator (CFTR) gene, reverse the consequences of the genetic defect on protein function, promote clearance of respiratory secretions, reduce or eliminate bacterial infection, and reduce the deleterious pulmonary inflammatory response. Those trials that are listed in the NIH Clinical Trials Registry will be designated by including their NCT identifier codes, and further details about each trial are available through links to that database.


The drive for developing gene therapy to treat CF began in earnest in 1989 with the identification and cloning of the CF transmembrane conductance regulator (CFTR) gene. Because mutations in CFTR account for virtually all cases of CF, correcting abnormalities in this single gene should theoretically cure the disease (see "Cystic fibrosis: Genetics and pathogenesis"). Despite early progress in the gene therapy field, many significant obstacles continue to interfere with the development of this approach as a treatment for CF. To overcome these barriers, research in this field is focusing on developing vectors for the safe delivery of a normal CFTR gene to the airways of patients with CF [2,3]. Vector efficiency, transgene persistence, and overcoming host immune responses remain critical issues in gene therapy for CF.

The UK Cystic Fibrosis Gene Therapy Consortium has been using a cationic lipid formulation (GL67A) to transfer a caffeoyl phenylethanoid glycoside (CpG)-free plasmid encoding functional human CFTR cDNA to the airway epithelium (where CpG-free refers to plasmids lacking a specific DNA sequence known to induce inflammation in experimental animals) [3]. Twelve monthly administrations of the lipid/plasmid formulation resulted in prolonged CFTR gene expression (>140 days) in the lungs of mice, with minimal toxicity [4]. Recently, the results of a randomized, double-blind, phase 2b clinical trial in CF subjects were reported [5]. Subjects with CF received a CFTR-containing plasmid in GL67A or placebo every 4 weeks for 48 weeks, and the primary endpoint was the relative change in percent predicted forced expiratory volume in one second (FEV1). A subgroup also received intranasal administrations so that nasal transepithelial potential difference could be tested to directly detect the successful generation of the CFTR channel. Subjects who received the CFTR-GL67A formulation demonstrated a modest 3.7 percent increase in percent predicted FEV1 at week 48 compared with the placebo group (95% CI 0.1%–7.3%; p = 0.046). The CFTR-GL67A-treated patients also had improvement in several secondary endpoints including forced vital capacity (FVC) and a CT measurement of gas trapping (p = 0.048). However, other secondary endpoints including quality of life were not different between the two groups. A subset of patients underwent bronchoscopy to evaluate CFTR gene expression. Vector-specific DNA was detected in 12 of 14 CFTR-GL67A-treated patients and was below the limit of measurement in all (n = 7) placebo samples (p = 0.00); however, there was no vector-specific mRNA detected in bronchial samples from either group. Nasal potential difference measurements did not change significantly during the study. In summary, these results indicate that substantial improvements to this approach will need to be made for it to move forward in the treatment of CF lung disease.

Preclinical work is also progressing on the development of lentivirus-based vectors [6] and adeno-associated virus-based vectors [7] for CFTR gene transfer to airway epithelium.


Ivacaftor, a small molecular weight compound developed to treat CFTR gating mutations, is the first mutation-specific drug to receive Food and Drug Administration (FDA) approval for use in CF (see "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'). This drug was initially approved for the treatment of patients with the G551D gating defect. Although the approval of ivacaftor represents a significant advance, the G551D mutation is present in only approximately 4 percent of CF patients and is merely one of approximately 2000 mutations that have been identified in human CF transmembrane conductance regulator (CFTR) alleles. More recently, ivacaftor has been found to have efficacy in patients with other gating mutations, and this drug is now approved for the treatment of the G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations.


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Literature review current through: Apr 2017. | This topic last updated: Sep 03, 2015.
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