Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis

Wilschanski, Michael; Miller, Langdon L.; Shoseyov, David; Blau, H.; Rivlin, Joseph; Aviram, Micha; Cohen, Michael; Armoni, S.; Yaakov, Yasmin; Pugatch, T.; Cohen‐Cymberknoh, Malena; Miller, Nilsen L.; Reha, A.; Northcutt, Valerie; Hirawat, Samit; Donnelly, Kenneth; Elfring, Gary L.; Ajayi, Temitayo; Kerem, Eitan

doi:10.1183/09031936.00120910

Cited by 184 publications

(152 citation statements)

References 46 publications

(70 reference statements)

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“…A phase II study in 19 adult patients with CF, having at least one CFTR nonsense mutation allele and an abnormal nasal total chloride transport, showed that ataluren three times daily improved total chloride transport (combined mean change of -5.4 mV, p,0.001), with an overall on-treatment response rate of 61% (p,0.001). There was also a nonsignificant trend towards improvement in forced expiratory volume in 1 s (FEV1) and a 23% reduction in cough (p50.006) by the end of the study (day 84) [46].…”

Section: Cftr Modulatorsmentioning

confidence: 98%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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Section: Cftr Modulatorsmentioning

confidence: 98%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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“…Consequently, aminoglycosides and ataluren have been explored as therapies for multiple genetic diseases caused by nonsense mutations, in which even a small amount of full-length functional protein may be sufficient to achieve a therapeutic effect. Clinical trials of these drugs have demonstrated some promise in Duchenne muscular dystrophy (DMD) and cystic fibrosis patients, although results have been inconsistent among trials (17)(18)(19).…”

Section: Significancementioning

confidence: 99%

Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3′ UTR

Goodenough

Robinson

Zook

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Aminoglycosides have been proposed as therapies for genetic disorders caused by nonsense mutations, because of their capacity to enhance translational read-through of premature termination codons (PTCs), thereby permitting expression of functional fulllength protein. However, a potential consequence of this strategy is the development of an autoimmune response to HLA-presented epitopes encoded downstream of the PTC or other stop codons. Using a recombinant virus-expression system in tissue culture and in mice, we demonstrate that gentamicin can induce expression and MHC class I presentation of a model epitope encoded downstream of a PTC at levels sufficient to activate CD8 + T cells. The degree of read-through-derived peptide presentation varies with the sequence of the stop codon and +1 nucleotide. Additionally, we applied a mass spectrometry exploration of the HLA class I peptide repertoire of gentamicin-treated cells and identified multiple peptides derived from read-through of conventional stop codons. These results substantiate the possibility of self-reactivity to cryptic epitopes revealed by stop codon read-through therapies and potentially other therapeutic approaches involving compounds that alter translational fidelity.recoding | antigen presentation | autoimmunity

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“…Ataluren has orphan status from the FDA and European Commission as well as Subpart E for expedited development from the FDA. The phase 3 trial data will become available in the first half of 2012 (Wilschanski et al, 2011; and http://www.ptcbio.com/3.1.1_genetic_disorders.aspx).…”

Section: Anti-inflammatoriesmentioning

confidence: 99%