R560S: A class II CFTR mutation that is not rescued by current modulators

Awatade, Nikhil T; Ramalho, Sofia; Silva, Iris; Felício, Verónica; Botelho, Hugo M.; Poel, Eyleen de; Vonk, Annelotte M.; Beekman, Jeffrey M.; Farinha, Carlos M.; Amaral, Margarida D.

doi:10.1016/j.jcf.2018.07.001

Cited by 28 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lumacaftor has demonstrated different efficiency and potency in rescuing other CFTR mutations causing protein misfolding. In cell lines, lumacaftor was able to rescue CFTR function for E92K, L1077P, and M1101K, although it had no effect on G85E, R560S, and N1303K (Avramescu et al, 2017;Lopes-Pacheco et al, 2017;Awatade et al, 2019). The correction effects were also variable in patients-derived specimens carrying the F508del mutation in one allele and a minimal function mutation in trans (i.e., in the second allele); the mutants A561E, Y1092X, and W1282X demonstrated a response to lumacaftor treatment (Awatade et al, 2014;Haggie et al, 2017), but no effect was found for E60X, 394delTT, 711-1G>T, G542X, 1717-1G>A, and N1303K, among others (Awatade et al, 2014;Dekkers et al, 2016a;Pranke et al, 2017).…”

Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 97%

“…Individuals with CF may nevertheless carry different CFTR mutations on the two alleles, leading to thousands of possible combinations of CF genotypes. Noteworthy, CFTR mutations may differently respond to the same intervention (e.g., correction by low temperature or by chemical compounds), even for those classified as belonging to the same defect class (Rapino et al, 2015;Dekkers et al, 2016a;Dekkers et al, 2016b;Lopes-Pacheco et al, 2016;Lopes-Pacheco et al, 2017;Han et al, 2018;Awatade et al, 2019). Therapeutic responses may also differ between individuals carrying the same CF genotypes (Boyle et al, 2014;Donaldson et al, 2018a;Keating et al, 2018;Matthes et al, 2018).…”

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

“…Both cysteamine and thymosin a-1 were also claimed to restore functional expression of F508del-CFTR (Tosco et al, 2016;Romani et al, 2017). Nevertheless, several independent CF research groups failed to demonstrate rescue of F508del-CFTR PM expression and function by either cysteamine or thymosin a-1 (Tomati et al, 2018b;Armirotti et al, 2019;Awatade et al, 2019). Although the immunomodulatory effect of these molecules in CF remains to be further exploited, they did not demonstrate F508del-CFTR correction.…”

Section: Identifying Feasible Solutions For a Cf Healthcare Cost Sustmentioning

confidence: 99%

See 2 more Smart Citations

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

2020

View full text Add to dashboard Cite

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.

show abstract

Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 97%

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

Section: Identifying Feasible Solutions For a Cf Healthcare Cost Sustmentioning

confidence: 99%

See 1 more Smart Citation

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

2020

View full text Add to dashboard Cite

show abstract

“…2). Similarly, trivial Band C expression is observed in the CF mutant R560T‐ (30, 50, 71) and R560S‐CFTR (72). Taken together, our own and previous data highlight the importance of H3, H4, and H5 helices for achieving normal CFTR processing.…”

Section: Discussionmentioning

confidence: 85%

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

et al. 2019

View full text Add to dashboard Cite

People with the genetic disease cystic fibrosis (CF) often carry a deletion mutation ∆F508 on the gene encoding the CF transmembrane conductance regulator (CFTR) Cl− channel. This mutation greatly reduces the CFTR maturation process and slows the channel opening rate. Here, we investigate whether residues near F508 contribute to these defects in ∆F508‐CFTR. Most deletion mutations, but not alanine substitutions, of individual residues from positions 503 to 513 impaired CFTR maturation. Interestingly, only protein processing of ∆Y512‐CFTR, like that of ∆F508‐CFTR, was greatly improved by low‐temperature culture at 27°C or small‐molecule corrector C18. The 2 mutant Cl− channels were equally slow to open, suggesting that they may share common structural flaws. Studies on the H3‐H4 loop that links residues F508 and Y512 demonstrate that G509A/V510G mutations, moving G5091 position backward in the loop, markedly enhanced ∆F508‐CFTR maturation and opening rate while promoting protein stability and persistence of the H3 helix in ∆F508 nucleotide‐binding domain 1. Moreover, V510A/S511A mutations noticeably increased ∆Y512‐CFTR maturation at 27°C and its opening rate. Thus, loop abnormalities may contribute to ∆F508‐ and ∆Y512‐CFTR defects. Importantly, correcting defects from G509 displacement in ∆F508‐CFTR may offer a new avenue for drug discovery and CF treatments.—Chen, X., Zhu, S., Zhenin, M., Xu, W., Bose, S. J., Wong, M. P.‐F., Leung, G. P. H., Senderowitz, H., Chen, J.‐H. A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation. FASEB J. 33, 5126–5142 (2019). http://www.fasebj.org

show abstract

“…Targeting select aspects of the CFTR interactome to encourage correct cellular homeostasis has given rise to a novel class of CFTR correctors termed proteostasis regulators, that may show additive benefit with other CFTR modulators [43,44]. However, the inferred benefit of using proteostasis regulators seems relevant for the Phe508del CFTR defect only, with little evidence suggesting other CF causing mutations will be impacted similarly [45]. Currently, these therapeutic small molecules are limited in the range of CFTR defects that they can treat, leaving a large subset of CF patients excluded from potential treatment.…”

Section: Current Treatment Options For Cfmentioning

confidence: 99%

Emerging gene therapies for cystic fibrosis

Miah

Hyde

Gill

2019

Expert Review of Respiratory Medicine

View full text Add to dashboard Cite

Introduction: Cystic Fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class. Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF. Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating Adenoviral vectors, Rapamycin loaded nanoparticles and lung-tropic lentiviral vectors. The characterisation of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and nonviral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

show abstract

R560S: A class II CFTR mutation that is not rescued by current modulators

Abstract: Altogether, these results indicate that R560S is a class II mutation. However, unlike F508del, it cannot be rescued by any of the CFTR modulators tested.

Cited by 28 publications

References 37 publications

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

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

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

Emerging gene therapies for cystic fibrosis

Contact Info

Product

Resources

About