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 backbone of in vitro cellular models to date, as well as improved expansion protocols to overcome finite supply of the cellular source. We highlight a range of strategies for establishment of three dimensional (3-D) airway and intestinal organoid models and evaluate the limitations and potential improvements in each system, focusing on their application in CF. The in vitro CFTR functional assays in patient-derived organoids allow for preclinical pharmacotherapy screening to identify responsive patients. It is likely that organoids will be an invaluable preclinical tool to unravel disease mechanisms, design novel treatments, and enable clinicians to provide personalized management for patients with CF.

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A significant challenge to making targeted cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q, with a potential role contributing to intrapore chloride ion permeation, in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using an ion transport assay and forskolin-induced swelling assay, respectively. CFTR potentiators (VX-770, GLPG1837, and VX-445) and correctors (VX-809, VX-445, with or without VX-661) were tested. Data from R352Q-CFTR were compared with data of 20 participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function that was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics simulations of R352Q-CFTR were carried out, which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico molecular dynamics simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine.

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BackgroundPatient-oriented research approaches that reflect the needs and priorities of those most affected by health research outcomes, improves translation of research findings into practice. Development of targeted therapies for Cystic Fibrosis (CF) is a viable treatment option now for some eligible individuals despite the heterogeneous patient-specific therapeutic response. This has necessitated development of a clinical tool that predicts treatment response for individual patients. Patient-derived mini-organs (organoids) have been at the forefront of this development. However, little is known about their acceptability in CF patients and members of the public.MethodsWe used a cross-sectional observational design to conduct an online survey in people with CF, their carers and community comparisons. Acceptability was examined in five domains; 1-willingness to use organoids, 2-perceived advantages and disadvantages of organoids, acceptable 3-out-of-pocket costs, 4-turnaround time, and 5-source of tissue.Results188 participants completed the questionnaire, including adults with CF and parents of children with CF (90(48%)), and adults without CF and parents of children without CF (98(52%)). Use of organoids to guide treatment decisions in CF was acceptable to 86(95%) CF participants and 98 (100%) community participants. The most important advantage was that organoids may improve treatment selection, improving the patient's quality of life and life expectancy. The most important disadvantage was that the organoid recommended treatment may be unavailable or too expensive.ConclusionsThese findings indicate acceptance of patient-derived organoids as a tool to predict treatment response by the majority of people surveyed. This may indicate successful future implementation into healthcare systems.

Museums play a vitally important role in supporting both informal and formal education and are important venues for fostering public understanding of evolution. The Yale Peabody Museum has implemented significant education programs on evolution for many decades, mostly focused on the museum's extensive collections that represent the past and present tree of life. Twelve years ago, the Peabody began a series of new programs that explored biodiversity and evolution as it relates to human health. Modern evolutionary theory contributes significantly to our understanding of health and disease, and medical topics provide many excellent and relevant examples to explore evolutionary concepts. The Peabody developed a program on vector-borne diseases, specifically Lyme disease and West Nile virus, which have become endemic in the United States. Both of these diseases have complex transmission cycles involving an intricate interplay among the pathogen, host, and vector, each of which is subject to differing evolutionary pressures. Using these stories, the museum explored evolutionary concepts of adaptation (e.g., the evolution of blood feeding), coevolution (e.g., the "arms race" between host and vector), and variation and selection (e.g., antibiotic resistance) among others. The project included a temporary exhibition and the development of curriculum materials for middle and high school teachers and students. The popularity of the exhibit and some formal evaluation of student participants suggested that this educational approach has significant potential to engage wide audiences in evolutionary issues. In addition it demonstrated how natural history museums can incorporate evolution into a broad array of programs.