High-Throughput Screening for Readthrough Modulators of CFTR PTC Mutations

Liang, Feng; Shang, Haibo; Jordan, Nikole Jolene; Wong, Eric C.; Mercadante, Dayna; Saltz, Josef; Mahiou, Jérôme; Bihler, Hermann; Mense, Martin

doi:10.1177/2472630317692561

Cited by 37 publications

(43 citation statements)

References 41 publications

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“…On the other hand, based on the knowledge gained from the molecular study, the implementation of the personalized medicine occurred, mainly, for the new read-through drugs, enhancers, CFTR protein stabilizers and amplifier compounds (Boyle and De Boeck, 2013; Ikpa et al, 2014; Marson et al, 2015; Quon and Wilcox, 2015; Corvol et al, 2016; De Boeck and Amaral, 2016; Lopes-Pacheco, 2016; Schmidt et al, 2016; Schneider et al, 2016; Spielberg and Clancy, 2016; Liang et al, 2017; Rafeeq and Murad, 2017) ( Figures 1, 2 ).…”

Section: Cystic Fibrosis Diseasementioning

confidence: 99%

Personalized or Precision Medicine? The Example of Cystic Fibrosis

Marson

2017

Front. Pharmacol.

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The advent of the knowledge on human genetics, by the identification of disease-associated variants, culminated in the understanding of human variability. With the genetic knowledge, the specificity of the clinical phenotype and the drug response of each individual were understood. Using the cystic fibrosis (CF) as an example, the new terms that emerged such as personalized medicine and precision medicine can be characterized. The genetic knowledge in CF is broad and the presence of a monogenic disease caused by mutations in the CFTR gene enables the phenotype–genotype association studies (including the response to drugs), considering the wide clinical and laboratory spectrum dependent on the mutual action of genotype, environment, and lifestyle. Regarding the CF disease, personalized medicine is the treatment directed at the symptoms, and this treatment is adjusted depending on the patient’s phenotype. However, more recently, the term precision medicine began to be widely used, although its correct application and understanding are still vague and poorly characterized. In precision medicine, we understand the individual as a response to the interrelation between environment, lifestyle, and genetic factors, which enabled the advent of new therapeutic models, such as conventional drugs adjustment by individual patient dosage and drug type and response, development of new drugs (read through, broker, enhancer, stabilizer, and amplifier compounds), genome editing by homologous recombination, zinc finger nucleases, TALEN (transcription activator-like effector nuclease), CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated endonuclease 9), and gene therapy. Thus, we introduced the terms personalized medicine and precision medicine based on the CF.

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Section: Cystic Fibrosis Diseasementioning

confidence: 99%

Personalized or Precision Medicine? The Example of Cystic Fibrosis

Marson

2017

Front. Pharmacol.

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“…Considering these challenges to readthrough, multi‐agent treatment for PTC mutants may be required, both to enhance readthough efficacy and augment activity of the readthrough product. Recently reported in vitro studies demonstrated that the readthrough efficiency can be substantially increased when administered in combination with CFTR correctors and potentiators . To broaden options, additional screens are in progress in several laboratories including our ongoing collaboration with Southern Research, and may yield novel chemical matter.…”

Section: Cftr Readthrough Agentsmentioning

confidence: 99%

“…Escin, an herbal compound is currently being explored, and arose out of a first‐generation screen . The incorporation of CFTR specific HRP assay in capacity to measure trafficking‐ competent readthrough products . Currently, efforts are being made to synthesize multiple scaffolds of hit agents to enhance the efficacy and potency, both alone and in combination with NMD inhibitors, correctors, and potentiators.…”

Section: Cftr Readthrough Agentsmentioning

confidence: 99%

“…Recently reported in vitro studies demonstrated that the readthrough efficiency can be substantially increased when administered in combination with CFTR correctors and potentiators. 50,59,60 To broaden options, additional screens are in progress in several laboratories including our ongoing collaboration with Southern Research, and may yield novel chemical matter. Escin, an herbal compound is currently being explored, and arose out of a firstgeneration screen.…”

Section: Cftr Readthrough Agentsmentioning

confidence: 99%

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Toward inclusive therapy with CFTR modulators: Progress and challenges

Guimbellot

Sharma

Rowe

2017

Pediatric Pulmonology

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Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre-clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cellbased tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation.

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“…For example, in the area of diagnostics and big data, a key breakthrough in exclusion-based sample preparation for individualized lung cancer data analytics and management will play a key role in designing treatment strategies in the clinic in a patient-specific manner. 1 In addition, high-throughput screening is being used to assess cystic fibrosis mutations, 2 demonstrating the importance of genome-based analytics toward personalizing care. Another exciting development is examining the use of cell culture assays to predict drug resistance in cancer therapy, which may help improve clinical actionability when alternative regimens are required.…”

mentioning

confidence: 99%

Making N-of-1 Medicine a Reality

Zarrinpar

2017

SLAS Technology

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High-Throughput Screening for Readthrough Modulators of CFTR PTC Mutations

Cited by 37 publications

References 41 publications

Personalized or Precision Medicine? The Example of Cystic Fibrosis

Personalized or Precision Medicine? The Example of Cystic Fibrosis

Toward inclusive therapy with CFTR modulators: Progress and challenges

Making N-of-1 Medicine a Reality

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