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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 2016 it had increased to 42 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 promising experimental therapies that have advanced to clinical trials. They include approaches to replace the abnormal Cystic fibrosis 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 Cystic fibrosis 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 impede the development of this approach as a treatment for CF including vector efficiency, transgene persistence, and evasion of host immune responses. To overcome these barriers, research in this field is focusing on developing more efficient and safe vectors [2,3].

The UK Cystic Fibrosis Gene Therapy Consortium has tested a cationic lipid formulation (GL67A) to transfer a cytosine-phosphate-guanine (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]. The results of a randomized, double-blind, phase 2b clinical trial in CF subjects have been reported [5]. Participants 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 assess for successful expression 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 progressing on the development of lentivirus-based [6] and adeno-associated virus-based [7] vectors for CFTR gene transfer to airway epithelium. Advancements in gene editing technology hold promise, but applications of techniques such as CRISPR/Cas to CF are in only very early stages of development [8].


Ivacaftor, a small molecular weight compound developed to treat CFTR class III (gating) mutations, was the first mutation-specific drug to receive Food and Drug Administration (FDA) approval for use in CF. This drug was initially approved for treatment of patients with the G551D gating defect and was then expanded to eight other gating mutations (G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). As of May 2017, the list was further expanded, so that ivacaftor is approved by the FDA for the treatment of 33 CFTR mutations (table 1) [9]   Although the approval of ivacaftor represented a remarkable advance, these gating and residual function mutations are present in only approximately 10 percent of CF patients. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Ivacaftor for G551D, other gating mutations, and residual function mutations'.)

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Literature review current through: Nov 2017. | This topic last updated: Jun 14, 2017.
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