Cystic fibrosis: Investigational therapies
- Richard H Simon, MD
Richard H Simon, MD
- Professor of Medicine
- University of Michigan Health Sciences Center
- Thomas H Sisson, MD
Thomas H Sisson, MD
- Professor of Medicine
- University of Michigan
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 . 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) . Twelve monthly administrations of the lipid/plasmid formulation resulted in prolonged CFTR gene expression (>140 days) in the lungs of mice, with minimal toxicity . Recently, the results of a randomized, double-blind, phase 2b clinical trial in CF subjects were reported . 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.
REVERSING THE CONSEQUENCES OF CFTR MUTATIONS ON PROTEIN FUNCTION
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.
- Cystic Fibrosis Foundation Annual Patient Registry Report, 2013. Available from the Cystic Fibrosis Foundation, at: http://www.cff.org/ (Accessed on December 15, 2014).
- Prickett M, Jain M. Gene therapy in cystic fibrosis. Transl Res 2013; 161:255.
- Griesenbach U, Alton EW. Progress in gene and cell therapy for cystic fibrosis lung disease. Curr Pharm Des 2012; 18:642.
- Alton EW, Boyd AC, Cheng SH, et al. Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung. Gene Ther 2014; 21:89.
- Alton EW, Armstrong DK, Ashby D, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015; 3:684.
- Griesenbach U, Inoue M, Meng C, et al. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med 2012; 186:846.
- Keswani SG, Balaji S, Le L, et al. Pseudotyped AAV vector-mediated gene transfer in a human fetal trachea xenograft model: implications for in utero gene therapy for cystic fibrosis. PLoS One 2012; 7:e43633.
- Wilschanski M, Miller LL, Shoseyov D, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J 2011; 38:59.
- Sermet-Gaudelus I, Boeck KD, Casimir GJ, et al. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 2010; 182:1262.
- Rowe S, Sermet-Gaudelus I, Konstan M, et al. Results of the phase 3 study of ataluren in nonsense mutation cystic fibrosis (NMCF) [Abstract 193]. Pediatr Pulmonol 2012; 47:290.
- Kerem E, Konstan MW, De Boeck K, et al. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2014; 2:539.
- Thomas PJ, Ko YH, Pedersen PL. Altered protein folding may be the molecular basis of most cases of cystic fibrosis. FEBS Lett 1992; 312:7.
- Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011; 108:18843.
- Clancy JP, Rowe SM, Accurso FJ, et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 2012; 67:12.
- Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142:718.
- Bilton D, Robinson P, Cooper P, et al. Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study. Eur Respir J 2011; 38:1071.
- Aitken ML, Bellon G, De Boeck K, et al. Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. Am J Respir Crit Care Med 2012; 185:645.
- Minutes from the Pulmonary-Allergy Drugs Advisory Committee (PADAC) of the Center for Drug Evaluation and Research, January 30, 2013. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM340156.pdf (Accessed on July 10, 2013).
- Minasian C, Wallis C, Metcalfe C, Bush A. Comparison of inhaled mannitol, daily rhDNase and a combination of both in children with cystic fibrosis: a randomised trial. Thorax 2010; 65:51.
- Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008; 372:415.
- Elborn JS, Geller D, Conrad D, et al. Phase 3 trial of inhaled levofloxacin (Aeroquin™, MP-376, APT-1026) vs. tobramycin inhalation solution (TIS) in intensively treated CF patients over 6 months. J Cyst Fibros 2013; 12:S35.
- Stuart Elborn J, Geller DE, Conrad D, et al. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J Cyst Fibros 2015; 14:507.
- Clancy JP, Dupont L, Konstan MW, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 2013; 68:818.
- Schuster A, Haliburn C, Döring G, et al. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68:344.
- Milla CE, Accurso FJ, Chmiel J, et al. Modulating Pseudomonas aeruginosa chronic inflammation with the anti-PcrV antibody KB001: Results of a pilot clinical and pharmacodynamic study In subjects with cystic fibrosis. Am J Respir Crit Care Med 2010; 181:A1845.
- Nichols DP, Konstan MW, Chmiel JF. Anti-inflammatory therapies for cystic fibrosis-related lung disease. Clin Rev Allergy Immunol 2008; 35:135.
- Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000; 16:534.
- Dauletbaev N, Fischer P, Aulbach B, et al. A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis. Eur J Med Res 2009; 14:352.
- Griese M, Kappler M, Eismann C, et al. Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. Am J Respir Crit Care Med 2013; 188:83.
- Griese M, Latzin P, Kappler M, et al. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J 2007; 29:240.
- Poschet JF, Timmins GS, Taylor-Cousar JL, et al. Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2007; 293:L712.
- GENE THERAPY
- REVERSING THE CONSEQUENCES OF CFTR MUTATIONS ON PROTEIN FUNCTION
- Class I mutations: Defective protein production
- Class II mutations: defective protein processing
- Class III mutations: Defective regulation
- Class IV mutations: Defective channels
- Combination strategy for the F508del mutation
- - Mutiple class mutation correctors
- CORRECTING ION FLUX ABNORMALITIES BY NON-CFTR TARGETED APPROACHES
- INHALED AGENTS TO RECONSTITUTE THE NORMAL AIRWAY SURFACE ENVIRONMENT
- ANTIBIOTICS AND ANTI-INFECTIVES
- Inhaled antibiotics
- Antibiotic treatment for eradication of MRSA
- Antipseudomonas antibody treatment
- ANTIINFLAMMATORY THERAPY
- INFORMATION FOR PATIENTS