Mutation-specific dual potentiators maximize rescue of CFTR gating mutants

Veit, Guido; Fonte, Dillon F. Da; Avramescu, Radu G.; Premchandar, Aiswarya; Bagdány, Miklós; Xu, Haijin; Bensinger, Dennis; Stubba, Daniel; Schmidt, Boris; Matouk, Elias; Lukacs, Gergely L.

doi:10.1016/j.jcf.2019.10.011

Cited by 33 publications

(36 citation statements)

References 41 publications

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“…Viable approaches to further increase the Trikafta therapy efficacy for F508del and rare CFTR mutant correction can be envisioned by implementing (a) triple corrector combinations ( 21 ), (b) combining correctors with a CFTR mRNA stabilizer (PTI428) ( 46 ) or dual potentiator ( 47 , 48 ), (c) increasing the constitutive CFTR activity ( 49 ), and/or (d) using potentiators that do not to compromise the biogenesis and stability of mutant CFTRs ( 35 , 50 ). Selection of modulator combinations, however, requires the knowledge of the mechanism of action of individual CFTR modulators.…”

Section: Discussionmentioning

confidence: 99%

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Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Veit¹,

Roldán²,

et al. 2020

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Based on its clinical benefits, Trikafta — the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) — was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator ( CFTR ) on at least 1 allele. Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) membrane spanning domains (MSDs) interface and NBD2, respectively, consistent with a type III corrector mechanism. This inference was supported by the VX-445 binding to and unfolding suppression of the isolated F508del-NBD1 of CFTR. The VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of WT CFTR in homozygous nasal epithelia. Substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K), confined to MSD1, MSD2, NBD1, and NBD2 of CFTR, was also observed in airway epithelia, suggesting an allosteric correction mechanism and the possible application of Trikafta for patients with rare misfolding mutants of CFTR.

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Section: Discussionmentioning

confidence: 99%

“…I sc measurement of polarized HNE has been described previously ( 21 , 48 ). HNE were exposed to compounds or 0.2% DMSO (vehicle control) for 24 hours at 37°C in serum-free PneumaCult-ALI medium (Stemcell Technologies).…”

Section: Methodsmentioning

confidence: 99%

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Veit¹,

Roldán²,

et al. 2020

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“…In recent years, a considerable effort was focused on molecular therapies that can directly interact with CFTR mutants has indicated the importance of identifying the mutations of CFTR and the complexity of CFTR mutant phenotypes at the cellular levels [ 10 , 30 , 31 ]. Moreover, early diagnosis through NBS is the best way to prevent primary and secondary manifestations of the disease.…”

Section: Discussionmentioning

confidence: 99%

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

Bozdoğan

Mujde

Boğa

et al. 2021

Genes

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Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.

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“…However, no significant improvements were observed in lung function of CF patients and adverse effects were also reported in many participants, resulting in early termination of this study. Recent studies have also demonstrated that co-administration of potentiators with complementary mechanisms of action may be an interesting approach for those CF-causing mutations in which CFTR gating/ conductance is not completely restored by single potentiators (Phuan et al, 2018;Veit et al, 2019).…”

Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Mutation-specific dual potentiators maximize rescue of CFTR gating mutants

Cited by 33 publications

References 41 publications

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

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