Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine.
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ABSTRACT:
SUBMITTER: Awatade NT
PROVIDER: S-EPMC6293199 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine.
Awatade Nikhil T NT Wong Sharon L SL Hewson Chris K CK Fawcett Laura K LK Kicic Anthony A Jaffe Adam A Waters Shafagh A SA
Frontiers in pharmacology 20181207
Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the ...[more]
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Project description: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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Project description:Rationale:Cultured human bronchial epithelia (HBE) are the gold standard model for assessing the efficacy of small molecule therapies in cystic fibrosis (CF). However, these cells are difficult to access, especially in young children. Human nasal epithelia (HNE) are used as a surrogate model although it is unknown whether HNE recapitulate the gene expression properties of HBE Objective: To investigate the similarities and differences in gene expression genome-wide between HBE and HNE with a focus on CF lung disease modifier genes. Methods: RNA-sequencing was conducted on paired cultured and naïve HNE and HBE (n=71 samples) collected from 21 patients with CF who underwent lung transplantation. Gene expression was first compared across cultured and naïve samples to assess the impact of the culturing process, then compared between cultured HNE and HBE. Co-expression relationships of CF modifier genes were compared between cultured HNE and HBE. Results: The culturing process had little impact on the expression level of CF lung disease modifier genes. These genes also showed significant equivalent expression between cultured HNE and HBE. Their co-expression relationships in cultured HNE and HBE overlapped significantly, suggesting the corresponding biological processes are consistent across the two tissues. Conclusions: CF lung disease modifier genes have similar expression profiles across cultured HNE and HBE. This supports the use of HNE as a surrogate airway model to investigate CF lung disease, modifier genes and enable investigation of CF precision medicine.
2021-11-15 | GSE172232 | GEO
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Project description: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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Project description:Cystic fibrosis is a deadly multiorgan disorder caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. More than 1,700 CFTR genetic variants exist that can cause CF, and majority of these are extremely rare. Because of genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogeneous patient pools. Also, the benefit of approved small-molecule CF modulators in a large number of rare mutation patients remains unknown. The goal of this study is to perform a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted human intestinal organoids (HIOs) to test CF modulator-Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in a (N = 1) clinical trial and showed improved clinical outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient-specific therapies could be easily identified and disease-relevant developmental abnormalities in CF organs could be studied and addressed.NEW & NOTEWORTHY In this study, we report an example of laboratory models informing clinical care for rare CF mutation patient, with subsequent recapitulation of clinical benefit in a unique and disease relevant, human-derived in vivo model, effectively translating data from the lab to the clinic and back. This extensive work outlines a potential platform to identify patient-specific therapies and to understand relevant developmental abnormalities associated with CF disease.
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Project description:Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting ~1 in 3,500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, more than 2,000 CFTR mutations have been identified, which produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small molecules, or modulators, that can restore CFTR function. In recent years, two modulators, ivacaftor (Kalydeco) and lumacaftor/ivacaftor (Orkambi), have been approved by the U.S. Food and Drug Administration to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators' efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients.
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