Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators

Wilde, Gert De; Gees, Maarten; Musch, Sara; Verdonck, Katleen; Jans, Mia; Wesse, Anne Sophie; Singh, Ankita; Hwang, Tzyh Chang; Christophe, Thierry; Pizzonero, Mathieu; Plas, Steven Van der; Desroy, Nicolas; Cowart, Marlon; Stouten, Pieter F. W.; Nelles, Luc; Conrath, Katja

doi:10.3389/fphar.2019.00514

Cited by 30 publications

(36 citation statements)

References 42 publications

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“…It was also highly functional in primary bronchial epithelial cells from a F508del-homozygous patient (Wang et al, 2018;Singh et al, 2019). ABBV-2737 was demonstrated to rescue functional expression of CFTR in F508del-expressing cells, and such effects were enhanced when it was co-administered with lumacaftor or ABBV-2222(de Wilde et al, 2019. ABBV-3221 also rescued CFTR function in F508del-expressing cells with a greater effect in combination with ABBV-2222 and ABBV-974 (Scanio et al, 2019).…”

Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 92%

“…Numerous libraries of compounds have been screened by distinct high-throughput screening (HTS) methods and using several cell models. These experimental approaches have been contributing to the identification of small-molecules from different chemical series (Pedemonte et al, 2005a;Van Goor et al, 2009;Van Goor et al, 2011;Phuan et al, 2014;Phuan et al, 2015;Liang et al, 2017;Giuliano et al, 2018;Van der Plas et al, 2018;Veit et al, 2018;Wang et al, 2018;Berg et al, 2019;De Wilde et al, 2019;Merket et al, 2019) (Figure 6). Notably, as cell background may significantly influence the pharmacological rescue of CFTR mutants (Pedemonte et al, 2010), most promising hits should be further validated in well-differentiated cells in order to identify non-cytotoxic and effective compounds that might result in optimal therapeutic benefits in the clinical scenario.…”

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

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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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Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 92%

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

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

2020

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“…In addition, the potential efficacy of novel compounds from academic groups or different pharmaceutical companies have also been revealed in Ussing chamber studies of patient-derived primary nasal epithelial cultures. Interestingly, our group and others observed that patients with the same genotype can exhibit different in-vitro drug responses (11,(25)(26)(27)(28)(29)(30). The molecular basis for interpatient variations in in-vitro response size remains unknown but is thought to be a harbinger of the extent of variability in clinical response size (15).…”

Section: Introductionmentioning

confidence: 85%

A new platform for high-throughput therapy testing on iPSC-derived, immature airway from Cystic Fibrosis Patients

Wellhauser

Laselva

et al. 2021

Preprint

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Induced pluripotent, stem cell (iPSC)-derived models of airway tissue have successfully modeled the primary defect in regulated chloride conductance caused by the major Cystic Fibrosis causing mutation, F508del. However, it remains unclear if iPSC-derived airway cultures can be used in high-throughput therapy development for F508del and rarer mutations. There is an urgent need for airway tissue models that reflect the variability of patient-specific responses and are scalable for therapy development. In the current work, we describe a robust, high-throughput fluorescence assay of mutant CFTR function in iPSCs differentiated to immature airway epithelium. This assay measures reproducible functional responses to modulators targeting either the major CF mutant F508del or the nonsense mutant: W1282X-CFTR. We show that the ranking of patient-specific responses to interventions in this stem-cell based model recapitulates the ranking observed in primary nasal epithelial cultures obtained from the same individuals. In summary, these proof-of-concept studies show that this novel platform has the potential to support therapy development and precision medicine for Cystic Fibrosis patients.

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“…ABBV-2737 is a second-generation corrector that was well-tolerated in phase I studies and demonstrated to rescue CFTR function in F508del/F508del HBE cells synergistically with VX-809, suggesting that these two molecules act by distinct mechanisms. 73 , 74 In a phase IIa study, ABBV-2737 led to a reduction in sweat Cl – concentration and improved ppFEV 1 , albeit modestly, in individuals with CF homozygous for F508del. 75 ABBV-3221 is another second-generation corrector that demonstrated rescue of F508del-CFTR function with greater effects when in combination with corrector ABBV-2222 and potentiator ABBV-974 (formerly GLPG1837).…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators

Cited by 30 publications

References 42 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 new platform for high-throughput therapy testing on iPSC-derived, immature airway from Cystic Fibrosis Patients

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

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