Class I defects account for single point mutations in DNA that inappropriately place a stop codon in the CFTR messenger RNA (mRNA) transcript and terminate the process of translation. The CFTR protein is left truncated, resulting in a loss of function at the apical layer of epithelial cells. These mutations are present in approximately 10% of patients with CF worldwide, and several novel therapies have been developed to target this specific population.
11
Tobramycin (Tobi; Novartis) is the bactericidal aminoglycoside antibiotic most commonly used today for coverage against severe gram-negative respiratory infections (eg,
P aeruginosa infection) in patients with CF.
13 Its mechanism is to interfere with bacterial proteins by binding to the 30S ribosomal RNA subunit during protein translation. Recent evidence suggests that aminoglycoside antibiotics can suppress premature termination codons by disrupting translational fdelity and allowing translation to continue to the normal termination of the transcript.
13 Aminoglycosides have additional dose-dependent pleiotropic effects whereby they induce “read-through” of premature stop codons, suppressing a premature stop codon and restoring synthesis to a full-length and functional CFTR protein.
14,15 Aminoglycoside binding to the ribosome enables read-through inducing misinterpretation of a stop codon, so that ultimately the stop codon directive is “ignored.”
16,17
Gentamicin was the first aminoglycoside investigated for this function.
14,15 Ex vivo administration of gentamicin was shown to increase CFTR function. In 2003, a double-blind, placebo-controlled trial
12 evaluated the use of topical nasal drops (gentamicin dose, 900 µg/d) to improve nasal respiratory function. This application significantly reduced the basal potential difference of nasal epithelium in both homozygous and heterozygous patients (n=19) with a stop codon defect (
P=.005).
7,12 Homozygous carriers of a nonsense mutation had a greater response to gentamicin, with apical CFTR function fully restored to nasal epithelial tissue in approximately 90% of patients. However, the high dosage needed to produce a clinically significant effect on chloride transport during systemic administration was a major limitation to the use of gentamicin (and other aminoglycosides). Although gentamicin has the pharmacologic potential to resolve several issues in CF, the required therapeutic dose has many toxic effects associated with long-term use, most notably renal and otovestibular effects.
11,12
At this publication, gentamicin and other amino-glycosides are not approved by the FDA for the sole purpose of CFTR modulation. However, many individuals with CF are treated with aminoglycosides (specifically tobramycin) for gram-negative pulmonary infections and not solely for modification of mutations.
13 Many physicians consider tobramycin the aminoglycoside of choice for managing lung infections associated with CF, with its pleiotropic effect in promoting CFTR modulation. We recommend using standard aminoglycoside dosing practices to manage the lung infections associated with CF, along with monitoring for renal toxic effects.
Ataluren (PTC 124; PTC Therapeutics),
18 currently recognized as an orphan drug by the FDA, is a more appealing therapeutic option for class I CFTR defects. In a mechanism similar to the pleiotropic effects of aminoglycosides, ataluren allows ribosomes to read through the mRNA premature stop codons, resulting in the translation of complete CFTR proteins.
19,20 Several phase II and III studies
19-21 have evaluated this drug’s efficacy and demonstrated improvements in nasal transepithelial potential differences, forced expiratory volume in 1 second (FEV
1), and weight gain in both adult and pediatric patient populations.
20 Adverse effects were generally mild, with gastrointestinal upset, headache, and dizziness most commonly reported (
Table 2). Because of its efficacy in targeting the underlying cause of CF and favorable adverse effect profile, ataluren is considered the more appropriate initial approach compared with aminoglycosides in patients with CF who have class I mutations.
10,21 Several phase III trials of ataluren are currently underway in patients with CF who are aged 6 years or older, to determine long-term safety and efficacy (
Table 3).
1,20 One phase III trial found that combining ataluren with tobramycin may reduce its efficacy, suggesting that this combination should not be used.
22 Another antibiotic would therefore need to replace tobramycin should a gram-negative infection develop in a patient receiving ataluren. In these situations, ideal antibiotic therapy would be based on culture and sensitivity results.