Review
CFTR Protein Repair Therapy in Cystic Fibrosis
Tratamientos reparadores de la proteína CFTR en la fibrosis quística
a Unidad de Fibrosis Quística, Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain
b Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
c Unidad de Fibrosis Quística, Servicio de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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"afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Unidad de Fibrosis Quística, Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Fibrosis Quística, Servicio de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamientos reparadores de la proteína CFTR en la fibrosis quística" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1760 "Ancho" => 3161 "Tamanyo" => 490268 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Types of mutations in cystic fibrosis.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The completion of the human genome project was a relevant milestone for medical knowledge, providing the information necessary for understanding the unique characteristics of each individual.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The logical consequence of this knowledge would be to be able to apply specific diagnostic tests and treatments to each patient based on their individual genetic information. This new form of medical care is called personalized medicine.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, despite the great progress that has led to the knowledge of the human genome, its translation into diagnostic and personalized treatments has been less than expected. At present, steps are being in this direction with two major initiatives: systems biology<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and pharmacogenetics.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The ultimate goal of these initiatives is to develop a medical practice customized to the characteristics of each individual that can predict the onset or course of a particular disease, allow appropriate prevention strategies to be established and, finally, enable the patient to take part in the decision making. This has been called P4 medicine.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Cystic fibrosis (CF) remains the most common and lethal genetic disease among Caucasians. It occurs at a rate of 1 in 2500–6000 newborns, depending on the region and ethnic origin, and in a proportion of healthy carriers, varying between 1:20 and 37.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In Spain, thanks to the progressive introduction of neonatal screening programs in the different communities, a lower incidence of CF is now being seen than was previously estimated in 2009, <span class="elsevierStyleItalic">i.e.</span>, 1/4430 live births in Galicia, 1/4339 in Castile-Leon, 1/5376 in Murcia, 1/5840 in Catalonia, and 1/6602 in the Balearic Islands.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It is estimated that there are 70<span class="elsevierStyleHsp" style=""></span>000 CF sufferers worldwide.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The disease is caused by mutations in the gene encoding the regulatory protein cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel involved in the release of adenosine triphosphate and regulation of other ion transport channels. This protein is expressed in respiratory epithelial cells, pancreas, biliary tract, sweat glands and genitourinary system. Its alteration leads to an abnormality in ion transport, so that patients produce thick, sticky mucus that clogs the ducts of the organ where it is located and so the alteration presents multisystemic effects that determine the wide range of clinical manifestations of CF. Despite major advances in the treatment of CF that have resulted in longer survival (present median is estimated in 37.5 years),<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> there is still a long way to go to ensure that patients with CF have a quantity and quality of life similar to that of subjects without the disease. In this context, new treatments to decrease morbidity and increase survival are necessary.</p><p id="par0015" class="elsevierStylePara elsevierViewall">CF is an example of a disease well-positioned to take advantage of personalized medicine. On one hand, it is a monogenic disease, caused by the mutations in a specific gene. The pathophysiology of the entity is well characterized and the therapeutic targets are clear. Furthermore, diagnosis of the disease requires genetic testing for the identification of the disease type, so the exact genetic defect is determined in each case.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">At present, two very different approaches are targeted at correcting the basic defect: gene therapy, aimed at correcting the genetic alteration, and molecule therapy, aimed at correcting the functional defect at the protein level. The focus of gene therapy is the introduction of normal gene copies in the airways of CF patients. It involves the insertion of a recombinant viral vector, the DNA of which has been extracted and replaced by the new therapeutic DNA. The viral vector serves as a vehicle for inserting the new DNA into the target cell. Various types of viruses, such as adenovirus or lentivirus, have been used to date. Furthermore, non-viral particles, such as nanoparticles capable of inserting DNA, have also been developed.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> However, the results so far have been poor, because the duration of expression of the introduced gene was short with both types of vectors.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The UK Gene Therapy Consortium is developing a phase II clinical trial to evaluate the clinical effectiveness of an optimized plasmidic/liposomal DNA vector.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The recruitment target is 130 patients and results are expected in 2014 (<a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01621867">NCT01621867</a>).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">On the other hand, therapy directed at restoring the function of the CFTR protein has been more successful. In recent years, results are beginning to come through on drugs that act directly on the CFTR protein. In fact, in January 2012, the first drug for correcting Gly551Asp mutation defects was marketed in the USA. In the following sections we will review the available information on the progress of personalized medicine for CF and available treatments aimed at correcting the defect causing the disease at the protein level. In this review, the nomenclature used for the description of CFTR gene mutations developed by the Human Genome Variation Society<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> will be used.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Mutations and Protein Defect</span><p id="par0030" class="elsevierStylePara elsevierViewall">CF is an autosomal recessive hereditary disease, so the mutation must be present in both copies of the CFTR gene to be affected. To date, over 1900 CFTR gene mutations associated with the disease have been identified in the coding sequence, messenger RNA or other elements. Mutations in the CFTR gene are available for consultation in the Cystic Fibrosis Mutation Database.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The first mutation described, and the most common worldwide, is Phe508del, but there are other specific mutations with varying frequency among different ethnic groups. In Spain, the average frequency of Phe508del mutation is between 50% and 60% of all of the studied chromosomes, the second most frequent is Gly542X with 4%–8%, followed by Asn1303Lys in 2%–4% of cases. The mutations described to date are classified into six types or classes according to the mechanism causing the disease.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> These types of mutations are summarized in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. Class I mutations lead to a premature stop codon in the messenger RNA which prevents translation of the complete protein. Thus, the protein produced is short and non-functioning. Class II mutations encode a structurally abnormal and misfolded protein that is removed by the endoplasmic reticulum before reaching the cell surface. The most common mutation in CF, Phe508del, belongs to this group. In the case of mutations in classes III to VI, proteins reach the cell surface, but do not function properly. Class III mutations cause a decreased channel activation, so channels remain closed. Class IV mutations cause a decrease in ion conductance through the channel. Class V mutations encode minor proteins resulting in a reduced amount of CFTR in the cell surface, so that a certain function occurs, but at a reduced level. Finally, class VI mutations lead to a shortened half-life due to protein instability and can also damage the regulation of neighboring CFTR channels in the cell surface.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">CFTR Modulators</span><p id="par0035" class="elsevierStylePara elsevierViewall">Three main classes have been identified in the development of drugs for repairing CFTR protein.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The first group are premature stop codon suppressors (class I mutations). These drugs prevent identification of this premature stop codon, so that protein synthesis can continue until completion. The second group are the CFTR correctors. These compounds are designed to correct defects in the transport of folded protein (class II mutations) to the cell membrane, where it may be able to function almost normally. The third group consists of the so-called CFTR potentiators. These are drugs designed to target the CFTR protein on the cell surface in order to improve its function. Thus, these potentiators can act on class III, IV, V and VI mutations. Currently, numerous molecules using these different mechanisms are under investigation, one of which has already reached the market: Ivacaftor (VX-770) is a CFTR potentiator approved in the USA in January 2012 for the treatment of CF patients older than 6 years of age who have the Gly551Asp mutation.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Class I Mutation Treatments</span><p id="par0040" class="elsevierStylePara elsevierViewall">Approximately 10% of CF cases are caused by class I mutations. The first drugs used for this class were aminoglycosides. Several years ago, gentamicin was reported to have the ability to mask the premature stop codon preventing synthesis of the CFTR protein. This is achieved by insertion of an amino acid that enables the ribosome to continue reading the gene, producing a full-length protein. Preclinical studies demonstrated that the protein could be synthesized in a mouse model and 35% of protein function was recovered <span class="elsevierStyleItalic">in vitro</span>.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18,19</span></a> The effect of the intravenous administration of gentamicin was assessed in two studies of CF patients with various types of class I mutations. One was conducted in the USA in five patients,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and another included 18 patients in France.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> However, although the response was positive, the results varied widely, so the benefit was not universal. Moreover, toxicity issues with aminoglycosides contributed to an unfavorable profile.</p><p id="par0045" class="elsevierStylePara elsevierViewall">A synthetic alternative is ataluren (PTC124; PTC Therapeutics, South Plainfield, NJ, USA). This is a molecule designed to enable ribosomes to read the genetic information while “skipping” the premature stop codon, producing a functional CFTR protein.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The pharmacokinetics of ataluren have been demonstrated in animal models and in phase II trials. In two small preliminary studies,<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23,24</span></a> a group of CF patients treated with oral ataluren showed improvement of the electrophysiological abnormalities of the disease, with an increase in the number of cells in the nose expressing the protein on their surface. Subsequently, another small study of 19 patients evaluated different doses of ataluren administered orally every 8<span class="elsevierStyleHsp" style=""></span>h, with improvements in CFTR activity and clinical parameters and a good safety profile.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The results of a phase III clinical trial of ataluren that had not yet been formally published were reported in the 2012 North American Cystic Fibrosis Conference. A total of 238 patients older than 6 years were randomized to receive ataluren 10, 10, 20<span class="elsevierStyleHsp" style=""></span>mg/kg or placebo every 8<span class="elsevierStyleHsp" style=""></span>h for 48 weeks. There were no significant differences in FEV<span class="elsevierStyleInf">1</span> in ataluren <span class="elsevierStyleItalic">versus</span> placebo after 48 weeks of treatment (−2.5% ataluren vs −5.5% placebo, <span class="elsevierStyleItalic">P</span>=ns). When stratified by chronic nebulized antibiotic use, there was a 6.7% difference in mean change after 48 weeks in favor of ataluren for patients not on tobramycin, while there was no difference in change in FEV<span class="elsevierStyleInf">1</span> in those receiving nebulized tobramycin. Something similar occurred with the percentage of exacerbations, where the difference between both groups was significant. When stratified, the patients in the ataluren group not on nebulized tobramycin showed a percentage decrease in exacerbations of 43% compared to the placebo group. Nasal potential difference and sweat chloride tests showed no difference between groups, irrespective of the use of nebulized antibiotics. The authors concluded that the benefits were greater in patients not receiving chronic antibiotic therapy with nebulized aminoglycoside, speculating that tobramycin and ataluren interacted at a ribosomal level, producing antagonism when used simultaneously.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Class II Mutation Treatments</span><p id="par0050" class="elsevierStylePara elsevierViewall">Class II mutations, being the most frequent mutation of the disease (Phe508del), are present in a large number of CF patients, making them a primary target in CF research. Various molecules have been studied, most of which have been developed by Vertex Pharmaceuticals Inc. The first corrector compound, lumacaftor (VX-809), showed good <span class="elsevierStyleItalic">in vitro</span> efficacy, improving chloride transport in 14%.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> However, the results were somewhat disappointing in patients, because the improvements in chloride concentration in sweat was very small (7<span class="elsevierStyleHsp" style=""></span>mmol/l) and there were no changes in nasal potential.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The effects of the CFTR potentiator ivacaftor (VX-770), a drug for class III mutations (see description below), have also been investigated in patients who were homozygous for Phe508del. The results of the DISCOVER study show that ivacaftor is not associated with a significant improvement in FEV<span class="elsevierStyleInf">1</span>, quality of life or the number of exacerbations <span class="elsevierStyleItalic">versus</span> placebo.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Since lumacaftor can assist the delivery of Phe508del-CFTR to the cell surface and ivacaftor increases opening time and chloride conduction through the epithelial cell, improvement of the underlying Phe508del defect may be possible with the combination of both molecules. <span class="elsevierStyleItalic">In vitro</span> studies of combined ivacaftor and lumacaftor in respiratory epithelia with Phe508del mutation have shown that lumacaftor increases CFTR chloride transport by 15% on its own, and when ivacaftor is added, transport increases to almost 30%. This combination of drugs has been investigated in a phase II study in patients with Phe508del mutation. Full results have not been yet published, but initial data suggest a beneficial effect on lung function in homozygous Phe508del, but not in heterozygosity.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Two clinical trials in patients 12 years or older homozygous for the mutation Phe508del are being developed to evaluate combined ivacaftor and lumacaftor; these are the TRAFFIC (<a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01807923">NCT01807923</a>)<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and TRANSPORT (<a id="intr0020" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01807949">NCT01807949</a>)<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> studies. The results might allow about half of the CF population to receive CFTR modulating therapy. However, studies are needed to evaluate the effect of combination therapy in Phe508del heterozygous individuals.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Another alternative is the corrector compound VX-661, and studies are currently ongoing. Its effectiveness is being tested alone and in combination with ivacaftor (VX-770) and the results will soon be available (<a id="intr0025" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01531673">NCT01531673</a>).<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Class III Mutation Treatments</span><p id="par0070" class="elsevierStylePara elsevierViewall">Ivacaftor (VX-770) is a CFTR potentiator that modulates the function of the abnormal protein.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> This molecule was originally designed to enhance CFTR function in cultures of respiratory epithelium cells carrying a single Gly551Asp mutation.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> It is the first drug approved in the USA and Europe for the treatment of CF in patients carrying the Gly551Asp mutation. After the capacity of ivacaftor to improve chloride transport through the cell membrane was demonstrated <span class="elsevierStyleItalic">in vitro</span>, the first phase II trials were conducted with 39 patients.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In this study, CFTR protein function improved three days after starting treatment, reaching chloride concentrations in sweat of up to normal levels. With these results, two further clinical studies followed: STRIVE study, in 144 patients aged 12 years or more<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and ENVISION study including 52 children between 6 and 11 years of age.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Both studies included patients with at least one Gly551Asp mutation and FEV<span class="elsevierStyleInf">1</span> between 40% and 105% that were initially followed for a period of 14 days and then randomized to receive 150<span class="elsevierStyleHsp" style=""></span>mg of oral ivacaftor or placebo twice a day for a period of 48 weeks. After completing 48 weeks of treatment, the patients were given the opportunity to continue in a longitudinal open-label study, the PERSIST study (<a id="intr0030" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01117012">NCT01117012</a>),<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> for 96 weeks.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In STRIVE, patients in the ivacaftor group had an improvement of 10.6% in FEV<span class="elsevierStyleInf">1</span> (primary endpoint) starting from day 15 of treatment, which was maintained during the 48-week study. Furthermore, a decrease in the chloride concentration in sweat was observed (mean: −48.7<span class="elsevierStyleHsp" style=""></span>mmol/L), with improved quality of life, a 55% reduction in exacerbations and a weight gain of 2.7<span class="elsevierStyleHsp" style=""></span>kg.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the ENVISION study coincide largely with those of the study in adolescents and adults, with the difference that quality of life did not reach statistical difference. The adverse effects more frequently observed in the treatment group in both STRIVE and ENVISION studies were upper respiratory tract infections, nasal congestion, sore throat, dizziness and skin rash. The preliminary results after the first 12 weeks of the PERSIST study reveal that improvements in lung function (FEV<span class="elsevierStyleInf">1</span>), respiratory symptoms, and weight gain among patients treated with ivacaftor are maintained during this period. Moreover, the subgroup of patients who switched from placebo to ivacaftor at baseline in PERSIST experienced a 10.8% improvement in FEV<span class="elsevierStyleInf">1</span> at 15 days, and 13% at 12 weeks, together with a reduction in exacerbations.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Despite the good results with ivacaftor in the treatment of the Gly551Asp mutation in children older than 6 years and adults at 48 weeks, some issues remain to be resolved. Firstly, the drug has not been tested in children under 6 years. However, it seems sensible to correct the defect before irreversible damage occurs, considering that lung involvement begins before the age of six. A trial in this age range is currently ongoing (<a id="intr0035" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01705145">NCT01705145</a>).<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Secondly, another alternative would be to also try other class III mutations. In this regard, <span class="elsevierStyleItalic">in vitro</span> studies on nine other mutations have shown very similar results,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> so it is reasonable to expect similar results in patients. There is an ongoing phase III clinical trial in patients older than 6 years with other class III mutations (KONTINUE and KONNECTION studies; <a id="intr0040" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01614470">NCT01614470</a>).<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42,43</span></a> Thirdly, although no treatment is available for the rest of the mutation classes (IV–VI), CFTR potentiators may be equally beneficial in these cases. A clinical trial is being conducted in this respect, evaluating the efficacy of ivacaftor in the Arg117His class IV mutation (KONDUCT study; <a id="intr0045" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01614457">NCT01614457</a>).<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Finally, effectiveness and long-term safety of ivacaftor beyond 48 weeks have not yet been established. The G551D Observational Study (GOAL; <a id="intr0050" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01521338">NCT01521338</a>)<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> is an observational study following patients older than 6 years receiving ivacaftor. It is aimed at reporting the efficacy and safety of long-term ivacaftor, along with other outcomes of interest that include inflammatory mediators in sputum, mucociliary clearance, and gastrointestinal pH. Results are expected in late 2013.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0090" class="elsevierStylePara elsevierViewall">CF is an example of a disease well-positioned to take advantage of personalized medicine. At present, two very different approaches aim to correct the basic defect: gene therapy aimed at correcting the genetic alteration, and therapy with molecules aimed at correcting the functional defect at the protein level. The latter is beginning to show promising results for various molecules in development, and one of them (ivacaftor) is already marketed for Gly551Asp class III mutation, with excellent results in children older than 6 years, adolescents and adults. The final objective is to provide corrector and potentiator treatments for all CF patients whatever their mutation. As the results of these and other new molecules appear, it is likely that a specific molecule or combination will be needed for each patient, depending on their existing mutations. In any case, the future is promising, and important steps have been taken toward obtaining a treatment that will effectively act on the cause of this disease.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres327148" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec308817" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres327147" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec308818" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Mutations and Protein Defect" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "CFTR Modulators" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Class I Mutation Treatments" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Class II Mutation Treatments" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Class III Mutation Treatments" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of Interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-06-17" "fechaAceptado" => "2013-07-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec308817" "palabras" => array:7 [ 0 => "Ataluren" 1 => "CFTR corrector" 2 => "CFTR modulator" 3 => "CFTR potentiator" 4 => "Cystic fibrosis transmembrane conductance regulator" 5 => "Ivacaftor" 6 => "Lumacaftor" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec308818" "palabras" => array:7 [ 0 => "Aatluren" 1 => "Fármaco corrector" 2 => "Fármaco modulador" 3 => "Fármaco potenciador" 4 => "Proteína reguladora de la conductabilidad transmembrana de la fibrosis quística" 5 => "Ivacaftor" 6 => "Lumacaftor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalized medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class <span class="elsevierStyleSmallCaps">i</span> mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class <span class="elsevierStyleSmallCaps">ii</span> mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class <span class="elsevierStyleSmallCaps">iii</span> mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La fibrosis quística es una enfermedad autosómica recesiva monogénica, de la que se han descrito ya más de 1.900 mutaciones agrupadas en 6 clases y que constituye un ejemplo de lo que podría ser una enfermedad bien situada para poder beneficiarse de la medicina personalizada. En la actualidad, 2 enfoques muy diferentes tienen por objetivo corregir el defecto básico: la terapia génica, dirigida a corregir la alteración genética, y la terapia encaminada a corregir el defecto a nivel de la proteína CFTR. Esta última comienza a dar resultados prometedores con diversas moléculas en desarrollo. Ataluren (PTC124) es una molécula diseñada para que los ribosomas se vuelvan menos sensibles a los codones de parada prematuros responsables de las mutaciones clase <span class="elsevierStyleSmallCaps">i</span>. Lumacaftor (VX-809) es un fármaco corrector que está dirigido a mutaciones de clase <span class="elsevierStyleSmallCaps">ii</span>, entre las que figura la más frecuente (Phe508del), con prometedores resultados. Ivacaftor (VX-770) es un fármaco potenciador, el único comercializado hasta el momento, que ha demostrado una buena eficacia para la mutación de clase <span class="elsevierStyleSmallCaps">iii</span>, Gly551Asp, en niños mayores de 6 años y adultos. Además, diversos ensayos están probando estos fármacos o la combinación de ellos para otras mutaciones genéticas menos frecuentes. En los últimos 5 años, la CFTR ha sido designado como una diana terapéutica. Ivacaftor es el primer fármaco que trata el defecto básico de la fibrosis quística, pero solo da respuesta a un escaso porcentaje de los pacientes. Se precisan nuevos fármacos capaces de restaurar la proteína CFTR causada por mutaciones más comunes.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Quintana-Gallego E, Delgado-Pecellín I, Calero Acuña C. Tratamientos reparadores de la proteína CFTR en la fibrosis quística. Arch Bronconeumol. 2014;50:146–150.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1760 "Ancho" => 3161 "Tamanyo" => 490268 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Types of mutations in cystic fibrosis.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Finishing the euchromatic sequence of the human, genome" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "International Human Genome Sequencing Consortium" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature03001" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2004" "volumen" => "431" "paginaInicial" => "931" "paginaFinal" => "945" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15496913" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical practice on the horizon: personalized medicine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 0 | 7 |
| 2024 October | 93 | 35 | 128 |
| 2024 September | 106 | 55 | 161 |
| 2024 August | 67 | 60 | 127 |
| 2024 July | 58 | 40 | 98 |
| 2024 June | 86 | 51 | 137 |
| 2024 May | 123 | 38 | 161 |
| 2024 April | 58 | 35 | 93 |
| 2024 March | 78 | 22 | 100 |
| 2024 February | 66 | 25 | 91 |
| 2023 May | 4 | 0 | 4 |
| 2023 March | 34 | 4 | 38 |
| 2023 February | 116 | 26 | 142 |
| 2023 January | 64 | 42 | 106 |
| 2022 December | 121 | 43 | 164 |
| 2022 November | 153 | 51 | 204 |
| 2022 October | 131 | 83 | 214 |
| 2022 September | 119 | 48 | 167 |
| 2022 August | 119 | 63 | 182 |
| 2022 July | 87 | 63 | 150 |
| 2022 June | 96 | 41 | 137 |
| 2022 May | 101 | 51 | 152 |
| 2022 April | 163 | 44 | 207 |
| 2022 March | 139 | 56 | 195 |
| 2022 February | 152 | 35 | 187 |
| 2022 January | 168 | 46 | 214 |
| 2021 December | 165 | 57 | 222 |
| 2021 November | 155 | 71 | 226 |
| 2021 October | 338 | 59 | 397 |
| 2021 September | 151 | 51 | 202 |
| 2021 August | 85 | 47 | 132 |
| 2021 July | 156 | 50 | 206 |
| 2021 June | 142 | 52 | 194 |
| 2021 May | 117 | 44 | 161 |
| 2021 April | 279 | 98 | 377 |
| 2021 March | 183 | 41 | 224 |
| 2021 February | 133 | 38 | 171 |
| 2021 January | 124 | 29 | 153 |
| 2020 December | 131 | 35 | 166 |
| 2020 November | 120 | 30 | 150 |
| 2020 October | 145 | 22 | 167 |
| 2020 September | 107 | 16 | 123 |
| 2020 August | 173 | 12 | 185 |
| 2020 July | 170 | 18 | 188 |
| 2020 June | 172 | 11 | 183 |
| 2020 May | 125 | 25 | 150 |
| 2020 April | 141 | 38 | 179 |
| 2020 March | 109 | 20 | 129 |
| 2020 February | 106 | 29 | 135 |
| 2020 January | 102 | 24 | 126 |
| 2019 December | 106 | 31 | 137 |
| 2019 November | 97 | 21 | 118 |
| 2019 October | 96 | 18 | 114 |
| 2019 September | 73 | 17 | 90 |
| 2019 August | 66 | 20 | 86 |
| 2019 July | 59 | 28 | 87 |
| 2019 June | 68 | 22 | 90 |
| 2019 May | 134 | 30 | 164 |
| 2019 April | 122 | 44 | 166 |
| 2019 March | 126 | 38 | 164 |
| 2019 February | 95 | 29 | 124 |
| 2019 January | 106 | 14 | 120 |
| 2018 December | 126 | 48 | 174 |
| 2018 November | 155 | 43 | 198 |
| 2018 October | 251 | 41 | 292 |
| 2018 September | 137 | 21 | 158 |
| 2018 May | 97 | 1 | 98 |
| 2018 April | 180 | 18 | 198 |
| 2018 March | 153 | 7 | 160 |
| 2018 February | 131 | 13 | 144 |
| 2018 January | 125 | 19 | 144 |
| 2017 December | 136 | 9 | 145 |
| 2017 November | 173 | 16 | 189 |
| 2017 October | 120 | 22 | 142 |
| 2017 September | 105 | 21 | 126 |
| 2017 August | 96 | 20 | 116 |
| 2017 July | 97 | 18 | 115 |
| 2017 June | 108 | 37 | 145 |
| 2017 May | 159 | 21 | 180 |
| 2017 April | 156 | 28 | 184 |
| 2017 March | 132 | 74 | 206 |
| 2017 February | 123 | 39 | 162 |
| 2017 January | 130 | 18 | 148 |
| 2016 December | 163 | 22 | 185 |
| 2016 November | 312 | 39 | 351 |
| 2016 October | 294 | 33 | 327 |
| 2016 September | 402 | 60 | 462 |
| 2016 August | 301 | 100 | 401 |
| 2016 July | 122 | 30 | 152 |
| 2016 June | 1 | 0 | 1 |
| 2016 March | 2 | 0 | 2 |
| 2016 February | 2 | 0 | 2 |
| 2015 December | 3 | 0 | 3 |
| 2015 October | 230 | 11 | 241 |
| 2015 September | 203 | 62 | 265 |
| 2015 August | 190 | 48 | 238 |
| 2015 July | 229 | 42 | 271 |
| 2015 June | 165 | 34 | 199 |
| 2015 May | 186 | 45 | 231 |
| 2015 April | 249 | 51 | 300 |
| 2015 March | 298 | 48 | 346 |
| 2015 February | 207 | 43 | 250 |
| 2015 January | 130 | 32 | 162 |
| 2014 December | 116 | 35 | 151 |
| 2014 November | 119 | 30 | 149 |
| 2014 October | 125 | 33 | 158 |
| 2014 September | 96 | 24 | 120 |
| 2014 August | 59 | 34 | 93 |
| 2014 July | 51 | 25 | 76 |
| 2014 May | 0 | 2 | 2 |
| 2014 April | 0 | 3 | 3 |
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