The Changing Face of Cystic Fibrosis and Its Implications for Screening.

Int J Neonatal Screen. 2020 Jul 03;6(3):

Authors: Naehrlich L

Abstract
Early diagnosis, multidisciplinary care, and optimized and preventive treatments have changed the face of cystic fibrosis. Life expectancy has been expanded in the last decades. Formerly a pediatric disease, cystic fibrosis has reached adulthood. Mutation-specific treatments will expand treatment options and give hope for further improvement of quality of life and life expectancy. Newborn screening for CF fits perfectly into these care structures and offers the possibility of preventive treatment even before symptoms occur. Especially in countries without screening, newborn screening will fulfill that promise only with increased awareness and new care structures.

PMID: 33239580 [PubMed]

Riociguat: clinical research and evolving role in therapy.

Br J Clin Pharmacol. 2020 Nov 26;:

Authors: Klinger JR, Chakinala MM, Langleben D, Rosenkranz S, Sitbon O

Abstract
Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance (6MWD) versus placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate (cGMP) synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has anti-fibrotic, anti-proliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension (PH), and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.

PMID: 33242341 [PubMed - as supplied by publisher]

Subtle relationships between Pseudomonas aeruginosa and fungi in patients with cystic fibrosis.

Acta Clin Belg. 2020 Nov 26;:1-11

Authors: Yan K, Yin H, Wang J, Cai Y

Abstract
Cystic fibrosis (CF) is one of the most common hereditary lung diseases. Pseudomonas aeruginosa (PA), Aspergillus fumigatus (AF) and Candida albicans (CA) are the principal bacterial and fungal pathogens in the airways of CF patients. The interactions of coexisting bacterial-fungal pathogens are of great interest. In the present work, we reviewed the literature of available in vitro and in vivo studies, whereas most of the reports have shown that PA inhibits the growth of fungi through restriction of iron uptake and secretion of toxic substances. Fungi may also affect the growth or virulence of PA through their secreted molecules. To clarify the bacterial-fungal interaction, more in-depth and detailed studies are still needed, which will provide a better understanding of species, microbial population dynamics, and related mechanisms in CF patients.

PMID: 33242290 [PubMed - as supplied by publisher]

Variations in Nutrition Practices in Cystic Fibrosis: A Survey of the DIGEST Program.

Nutr Clin Pract. 2020 Nov 26;:

Authors: Shaikhkhalil AK, Freeman AJ, Sathe M

Abstract
BACKGROUND: Evidence-based management of gastrointestinal (GI) and nutrition manifestations of cystic fibrosis (CF) is limited, and practice variations have not been studied.
METHODS: Thus, a survey was developed with the purpose of evaluating current nutrition practices of CF-focused gastroenterologists, specifically utilizing awardees and mentors of the Cystic Fibrosis Foundation (CFF) Developing Innovative GastroEnterology Specialty Training (DIGEST) Program. Topics included appetite stimulation, tube feeding (TF), and aspects of nutrition assessment, specifically urine sodium and essential fatty acid (EFA) status.
RESULTS: The response rate was 61% (22/36). About half (55%; 12/22) of respondents had 5-10 years of experience in GI, and 23% (5/22) had >10 years. In regard to appetite stimulation, the majority used cyproheptadine; however, duration and pattern of prescribing varied. Variation was noted in TF management pertaining to tube placement, formula choice, and prescribing pancreatic enzyme replacement therapy with overnight TF. The majority did not check EFAs or urine sodium. Treatment for deficiencies in EFA or abnormal urine sodium was inconsistent.
CONCLUSION: The survey reveals wide variation in management of some aspects of nutrition-related manifestations of CF among experienced providers. This reflects the need for research to provide evidence-based guidelines.

PMID: 33242217 [PubMed - as supplied by publisher]

Technology-Enabled Health Care Collaboration in Pediatric Chronic Illness: Pre-Post Interventional Study for Feasibility, Acceptability, and Clinical Impact of an Electronic Health Record-Linked Platform for Patient-Clinician Partnership.

JMIR Mhealth Uhealth. 2020 Nov 26;8(11):e11968

Authors: Opipari-Arrigan L, Dykes DMH, Saeed SA, Thakkar S, Burns L, Chini BA, McPhail GL, Eslick I, Margolis PA, Kaplan HC

Abstract
BACKGROUND: Mobile health (mHealth) technology has the potential to support the Chronic Care Model's vision of closed feedback loops and patient-clinician partnerships.
OBJECTIVE: This study aims to evaluate the feasibility, acceptability, and short-term impact of an electronic health record-linked mHealth platform (Orchestra) supporting patient and clinician collaboration through real-time, bidirectional data sharing.
METHODS: We conducted a 6-month prospective, pre-post, proof-of-concept study of Orchestra among patients and parents in the Cincinnati Children's Hospital inflammatory bowel disease (IBD) and cystic fibrosis (CF) clinics. Participants and clinicians used Orchestra during and between visits to complete and view patient-reported outcome (PRO) measures and previsit plans. Surveys completed at baseline and at 3- and 6-month follow-up visits plus data from the platform were used to assess outcomes including PRO completion rates, weekly platform use, disease self-efficacy, and impact on care. Analyses included descriptive statistics; pre-post comparisons; Pearson correlations; and, if applicable, effect sizes.
RESULTS: We enrolled 92 participants (CF: n=52 and IBD: n=40), and 73% (67/92) completed the study. Average PRO completion was 61%, and average weekly platform use was 80%. Participants reported improvement in self-efficacy from baseline to 6 months (7.90 to 8.44; P=.006). At 6 months, most participants reported that the platform was useful (36/40, 90%) and had a positive impact on their care, including improved visit quality (33/40, 83%), visit collaboration (35/40, 88%), and visit preparation (31/40, 78%). PRO completion was positively associated with multiple indicators of care impact at 3 and 6 months.
CONCLUSIONS: Use of an mHealth tool to support closed feedback loops through real-time data sharing and patient-clinician collaboration is feasible and shows indications of acceptability and promise as a strategy for improving pediatric chronic illness management.

PMID: 33242014 [PubMed - as supplied by publisher]

Aerosolized drug-loaded nanoparticles targeting migration inhibitory factors inhibit Pseudomonas aeruginosa-induced inflammation and biofilm formation.

Nanomedicine (Lond). 2020 Nov 26;:

Authors: Doroudian M, O'Neill A, O'Reilly C, Tynan A, Mawhinney L, McElroy A, Webster SS, MacLoughlin R, Volkov Y, E Armstrong M, A O'Toole G, Prina-Mello A, C Donnelly S

Abstract
Aim: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, which has been shown to promote disease severity in cystic fibrosis. Methods: In this study, aerosolized drug-loaded nanoparticles containing SCD-19, an inhibitor of MIF's tautomerase enzymatic activity, were developed and characterized. Results: The aerosolized nanoparticles had an optimal droplet size distribution for deep lung deposition, with a high degree of biocompatibility and significant cellular uptake. Conclusion: For the first time, we have developed an aerosolized nano-formulation against MIF's enzymatic activity that achieved a significant reduction in the inflammatory response of macrophages, and inhibited Pseudomonas aeruginosa biofilm formation on airway epithelial cells. This represents a potential novel adjunctive therapy for the treatment of P. aeruginosa infection in cystic fibrosis.

PMID: 33241979 [PubMed - as supplied by publisher]

Lung Clearance Index in Children with Sickle Cell Disease.

Pediatr Pulmonol. 2020 Nov 26;:

Authors: Machogu EM, Khurana M, Kaericher J, Clem CC, Slaven JE, Hatch JE, Davis SD, Peterson-Carmichael S

Abstract
INTRODUCTION: The Lung Clearance Index (LCI) derived from the multiple-breath washout test (MBW), is both feasible and sensitive to early lung disease detection in young children with cystic fibrosis and asthma. The utility of LCI has not been studied in children with sickle cell disease (SCD). We hypothesized that children with SCD, with or without asthma or airway hyper-reactivity (AHR), would have an elevated LCI compared to healthy controls.
METHODS: Children with SCD from a single center between the ages of 6-18 years were studied at baseline health and completed MBW, spirometry, plethysmography and blood was drawn for serum markers. Results were compared to healthy controls of similar race, age and gender.
RESULTS: Healthy controls (n=35) had a significantly higher daytime oxygen saturation level, weight and body mass index (BMI) but not height compared to participants with SCD (n=34). Total Lung Capacity (TLC) z-scores were significantly higher in the healthy controls compared to those with SCD (0.87 (1.13) vs 0.02 (1.27), p=0.005) while differences in Forced Expiratory Volume in 1 second (FEV1 ) z-scores approached significance (0.26 (0.97) vs -0.22 (1.09), p=0.055). There was no significant difference in LCI between the healthy controls compared to participants with SCD (7.29 (0.72) vs 7.40 (0.69), p=0.514).
CONCLUSION: LCI did not differentiate SCD from healthy controls in children between the ages of 6 and 18 years at baseline health. TLC may be an important pulmonary function measure to follow longitudinally in the pediatric SCD population. This article is protected by copyright. All rights reserved.

PMID: 33241925 [PubMed - as supplied by publisher]

Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue.

Sci Rep. 2020 Nov 25;10(1):20553

Authors: Hodos RA, Strub MD, Ramachandran S, Li L, McCray PB, Dudley JT

Abstract
Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue ΔF508-CFTR function yet remain poorly understood. Improved understanding of both the altered state of CF cells and the mechanisms of existing rescue strategies could reveal novel therapeutic strategies. Toward this aim, we measured transcriptional profiles of established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR and also re-analyzed public datasets characterizing transcription in human CF vs. non-CF samples from airway and whole blood. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these through the lens of prior knowledge, we compiled a "CFTR Gene Set Library" from literature. The core disease signature revealed remarkably strong connections to genes with established effects on CFTR trafficking and function and suggested novel roles of EGR1 and SGK1 in the disease state. Our data also revealed an unexpected mechanistic link between several genetic rescue interventions and the unfolded protein response. Finally, we found that C18, an analog of the CFTR corrector compound Lumacaftor, induces almost no transcriptional perturbation despite its rescue activity.

PMID: 33239626 [PubMed - in process]

Pseudomonas Quinolone Signal-Induced Outer Membrane Vesicles Enhance Biofilm Dispersion in Pseudomonas aeruginosa.

mSphere. 2020 Nov 25;5(6):

Authors: Cooke AC, Florez C, Dunshee EB, Lieber AD, Terry ML, Light CJ, Schertzer JW

Abstract
Bacterial biofilms are major contributors to chronic infections in humans. Because they are recalcitrant to conventional therapy, they present a particularly difficult treatment challenge. Identifying factors involved in biofilm development can help uncover novel targets and guide the development of antibiofilm strategies. Pseudomonas aeruginosa causes surgical site, burn wound, and hospital-acquired infections and is also associated with aggressive biofilm formation in the lungs of cystic fibrosis patients. A potent but poorly understood contributor to P. aeruginosa virulence is the ability to produce outer membrane vesicles (OMVs). OMV trafficking has been associated with cell-cell communication, virulence factor delivery, and transfer of antibiotic resistance genes. Because OMVs have almost exclusively been studied using planktonic cultures, little is known about their biogenesis and function in biofilms. Several groups have shown that Pseudomonas quinolone signal (PQS) induces OMV formation in P. aeruginosa Our group described a biophysical mechanism for this and recently showed it is operative in biofilms. Here, we demonstrate that PQS-induced OMV production is highly dynamic during biofilm development. Interestingly, PQS and OMV synthesis are significantly elevated during dispersion compared to attachment and maturation stages. PQS biosynthetic and receptor mutant biofilms were significantly impaired in their ability to disperse, but this phenotype was rescued by genetic complementation or exogenous addition of PQS. Finally, we show that purified OMVs can actively degrade extracellular protein, lipid, and DNA. We therefore propose that enhanced production of PQS-induced OMVs during biofilm dispersion facilitates cell escape by coordinating the controlled degradation of biofilm matrix components.IMPORTANCE Treatments that manipulate biofilm dispersion hold the potential to convert chronic drug-tolerant biofilm infections from protected sessile communities into released populations that are orders-of-magnitude more susceptible to antimicrobial treatment. However, dispersed cells often exhibit increased acute virulence and dissemination phenotypes. A thorough understanding of the dispersion process is therefore critical before this promising strategy can be effectively employed. Pseudomonas quinolone signal (PQS) has been implicated in early biofilm development, but we hypothesized that its function as an outer membrane vesicle (OMV) inducer may contribute at multiple stages. Here, we demonstrate that PQS and OMVs are differentially produced during Pseudomonas aeruginosa biofilm development and provide evidence that effective biofilm dispersion is dependent on the production of PQS-induced OMVs, which likely act as delivery vehicles for matrix-degrading enzymes. These findings lay the groundwork for understanding OMV contributions to biofilm development and suggest a model to explain the controlled matrix degradation that accompanies biofilm dispersion in many species.

PMID: 33239369 [PubMed - in process]

"Molecular Mechanisms for the Inflammation-Resolving Actions of Lenabasum".

Mol Pharmacol. 2020 Nov 25;:

Authors: Burstein S

Abstract
A first-in- class cannabinoid analog called lenabasum that is a CB2 agonist is being developed as an inflammation-resolving drug candidate. Thus far specific therapeutic targets include scleroderma, cystic fibrosis, dermatomyositis and lupus all of which represent unmet medical needs. Two somewhat independent molecular mechanisms for this type of action are here proposed. Both pathways initially involve the release of free arachidonic acid following activation of the CB2 receptor and PLA2 by lenabasum. The pathways then diverge into a COX-2 mediated and a lipoxygenase mediated route. The former leads to increased levels of the cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin-J2 that can activate the NLPR3 inflammasome, which, in turn releases caspase-3 leading to apoptosis and the resolution of chronic inflammation. The lipoxygenase mediated pathway stimulates the production of lipoxin A4 as well as other signaling molecules called specialized pro-resolving mediators (SPMs). These also have inflammation-resolving actions. It is not well understood under which conditions each of these mechanisms operate and if there is cross-talk between them. Thus, much remains to be learned about the mechanisms describing the actions of lenabasum. Significance Statement The resolution of chronic inflammation is a major unmet medical need. The synthetic non-psychoactive cannabinoid lenabasum could provide a safe and effective drug for this purpose. Two putative molecular mechanisms are suggested to better understand how lenabasum produces this action. In both different metabolites of arachidonic acid act as mediators.

PMID: 33239333 [PubMed - as supplied by publisher]

CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases.

Mol Ther. 2020 Sep 20;:

Authors: Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C

Abstract
At present, the idea of genome modification has revolutionized the modern therapeutic research era. Genome modification studies have traveled a long way from gene modifications in primary cells to genetic modifications in animals. The targeted genetic modification may result in the modulation (i.e., either upregulation or downregulation) of the predefined gene expression. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated nuclease 9 (Cas9) is a promising genome-editing tool that has therapeutic potential against incurable genetic disorders by modifying their DNA sequences. In comparison with other genome-editing techniques, CRISPR-Cas9 is simple, efficient, and very specific. This enabled CRISPR-Cas9 genome-editing technology to enter into clinical trials against cancer. Besides therapeutic potential, the CRISPR-Cas9 tool can also be applied to generate genetically inhibited animal models for drug discovery and development. This comprehensive review paper discusses the origin of CRISPR-Cas9 systems and their therapeutic potential against various genetic disorders, including cancer, allergy, immunological disorders, Duchenne muscular dystrophy, cardiovascular disorders, neurological disorders, liver-related disorders, cystic fibrosis, blood-related disorders, eye-related disorders, and viral infection. Finally, we discuss the different challenges, safety concerns, and strategies that can be applied to overcome the obstacles during CRISPR-Cas9-mediated therapeutic approaches.

PMID: 33238136 [PubMed - as supplied by publisher]

Inhibition of the GDP-d-Mannose Dehydrogenase from Pseudomonas aeruginosa Using Targeted Sugar Nucleotide Probes.

ACS Chem Biol. 2020 Nov 25;:

Authors: Beswick L, Dimitriou E, Ahmadipour S, Zafar A, Rejzek M, Reynisson J, Field RA, Miller GJ

Abstract
Sufferers of cystic fibrosis are at extremely high risk for contracting chronic lung infections. Over their lifetime, one bacterial strain in particular, Pseudomonas aeruginosa, becomes the dominant pathogen. Bacterial strains incur loss-of-function mutations in the mucA gene that lead to a mucoid conversion, resulting in copious secretion of the exopolysaccharide alginate. Strategies that stop the production of alginate in mucoid Pseudomonas aeruginosa infections are therefore of paramount importance. To aid in this, a series of sugar nucleotide tools to probe an enzyme critical to alginate biosynthesis, guanosine diphosphate mannose dehydrogenase (GMD), have been developed. GMD catalyzes the irreversible formation of the alginate building block, guanosine diphosphate mannuronic acid. Using a chemoenzymatic strategy, we accessed a series of modified sugar nucleotides, identifying a C6-amide derivative of guanosine diphosphate mannose as a micromolar inhibitor of GMD. This discovery provides a framework for wider inhibition strategies against GMD to be developed.

PMID: 33237714 [PubMed - as supplied by publisher]

Phospholipase C controls chloride-dependent short-circuit current in human bronchial epithelial cells.

Am J Physiol Lung Cell Mol Physiol. 2020 Nov 25;:

Authors: Grebert C, Becq F, Vandebrouck C

Abstract
Chloride secretion by airway epithelial cells is primordial for water and ion homeostasis and airways surface prevention of infections. This secretion is impaired in several human diseases, including cystic fibrosis, a genetic pathology due to CFTR gene mutations leading to chloride channel defects. A potential therapeutic approach is aiming at increasing chloride secretion either by correcting the mutated CFTR itself or by stimulating non-CFTR chloride channels at the plasma membrane. Here we studied the role of phospholipase C in regulating the transepithelial chloride secretion in human airway epithelial 16HBE14o- and CFBE cells over expressing WT‑ or F508del‑CFTR. Western blot analysis shows expression of the three endogenous PLC isoforms PLCd1, PLCg1 and PLCb3 in 16HBE14o‑ cells. In 16HBE14o‑ cells we performed Ussing chamber experiments after silencing each of these PLC isoforms or using the PLC inhibitor U73122 or its inactive analogue U73343. Our results show the involvement of PLCb3 and PLCg1 in CFTR-dependent short-circuit current activated by forskolin, but not PLCd1. In CFBE-WT CFTR and corrected CFBE‑F508del CFTR cells, PLCb3 silencing also inhibits CFTR‑dependent current activated by forskolin and UTP-activated calcium-dependent chloride channels (CaCC). Our study supports the importance of PLC in maintaining CFTR‑dependent chloride secretion over time, getting maximal CFTR-dependent current and increasing CaCC activation in bronchial epithelial cells.

PMID: 33236921 [PubMed - as supplied by publisher]

Physical Activity, Sedentary Time and Sleep in Cystic Fibrosis Youth: A Bi-Directional Relationship?

Pediatr Pulmonol. 2020 Nov 25;:

Authors: McNarry MA, Stevens D, Stone M, Roberts S, Hall S, Mackintosh KA

Abstract
PURPOSE: Physical activity (PA) and sleep are highly important for those with Cystic Fibrosis (CF), yet, despite this and suggestions of a bidirectional relationship between these factors in healthy children, their relationship is yet to be investigated.
METHODS: PA, sedentary time (SED) and sleep were objectively derived over seven days in 58 youth (11.9±2.7 years; 29 CF). Generalized linear latent and mixed models with a random intercept and slope at child-level were adjusted for age, sex, wear-time, type of day, group and mean PA/SED and sleep.
RESULTS: Every additional 10 mins sedentary was associated with 5.6 and 5.0 mins less sleep and 10.6 and 12.0 mins less wake after sleep onset (WASO) that night, in CF and healthy children, respectively. PA, regardless of intensity, was not associated with total sleep time but every additional 10 mins of light PA (LPA) was associated with 3.0 mins less WASO in healthy participants. Ten mins more sleep was associated with 3.1 and 1.7 mins less SED in CF and healthy children, respectively. In CF, greater sleep time led to less LPA (3.6 mins) the following day, whereas, in healthy children, poor sleep quality (greater WASO) was associated with more LPA (1.4 mins) and moderate-to-vigorous PA (5.2 mins) the following day.
CONCLUSION: A bidirectional relationship between SED and subsequent total sleep time was evident, irrespective of group, whereas the relationship between sleep and PA was group dependent. These findings have important implications regarding the reciprocal effects of promoting PA or sleep quantity or quality. This article is protected by copyright. All rights reserved.

PMID: 33236848 [PubMed - as supplied by publisher]

Allergic bronchopulmonary aspergillosis in children.

Pediatr Allergy Immunol. 2020 Nov;31 Suppl 26:20-22

Authors: Manti S, Fabio Parisi G, Papale M, Licari A, Chiappini E, Mulè E, Rotolo N, Leonardi S

Abstract
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy although there is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such as omalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach.

PMID: 33236425 [PubMed - in process]

Emerging Alternatives to Conventional Clinic Visits in the Era of COVID-19: Adoption of Telehealth at VCU Adult Cystic Fibrosis Center.

Int J Gen Med. 2020;13:1175-1186

Authors: Womack C, Farsin R, Farsad M, Chaudary N

Abstract
Cystic fibrosis (CF) is a genetic disease in which consistent follow-up care is required to avoid a decline in pulmonary and nutritional health. It is believed that if a CF patient ceases treatment for 2 days, this can result in an exacerbation. One week of missed treatments can result in a hospitalization and 1 month of missed treatments can result in an earlier demise. With a global pandemic that has affected more than 9 million people, many CF clinics were required to take steps to avoid transmission of this dangerous virus. This may result in delays in delivery of timely CF care due to closure of clinics and pulmonary function testing (PFT) laboratories and limited staff allowed on site for conducting in-person visits. These measures, along with suggestions from the Cystic Fibrosis Foundation (CFF) to extend the social distancing longer than traditional CDC recommendations for the CF community, create an urgent need to explore novel ways to deliver safer care via new standards in chronic health conditions like CF. Especially, as these preventive strategies may be necessary for long-term maintenance, few objective alternatives exist to guide clinicians and allied health professionals in CF centers how to proceed in this new era. This also presents an opportunity for novel approaches that could improve delivery of CF care with remote monitoring and real-time delivery of care in patients' home environments. Such emerging approaches could benefit patient care, leading to reduced costs and readmissions and improved access to care, medication adherence, and patient communication. We summarize our own experience and discuss the emerging delivery of CF care which can be generalizable to other pulmonary illnesses.

PMID: 33235489 [PubMed]

Letter to the editor of JCF.

J Cyst Fibros. 2020 05;19(3):503

Authors: Amaral MD

PMID: 32600655 [PubMed - indexed for MEDLINE]

Decoding (patho-)physiology of the lung by advanced in vitro models for developing novel anti-infectives therapies.

Drug Discov Today. 2020 Nov 21;:

Authors: Montefusco-Pereira CV, Carvalho-Wodarz CS, Seeger J, Kloft C, Michelet R, Lehr CM

Abstract
The need for novel anti-infective therapies is dramatically increasing, not only for viral but also for bacterial infections and antimicrobial resistance. This is especially true for chronic lung infections, typically occurring during e.g., cystic fibrosis (CF). Mimicking the structure and physiology of the diseased lung, advanced in vitro models also allow studying the pathophysiological changes relevant to microbial growth, drug resistance, and biofilm formation. Combining data from such advanced in vitro models with pharmacometric approaches may enable mechanistic explanation of the PK/PD drug exposure-response relationship and facilitate the translation to an in vivo setting.

PMID: 33232842 [PubMed - as supplied by publisher]

Animal and Cell Culture Models for Cystic Fibrosis: Which Model is Right for Your Application?

Am J Pathol. 2020 Nov 21;:

Authors: McCarron A, Parsons D, Donnelley M

Abstract
Over the last 30 years a range of cystic fibrosis (CF) animal models have been generated for research purposes. Species including mice, rats, ferrets, rabbits, pigs, sheep, zebrafish and fruit flies have all been used to model CF disease. Access to such a variety of animal models is a luxury for any research field, but it also complicates the decision-making process when it comes to selecting the right model for an investigation. The purpose of this review is to provide a guide for selecting the most appropriate CF animal model for any given application. In this review, the characteristics and phenotypes of each animal model are described, along with a discussion of the key considerations that must be taken into account when choosing a suitable animal. Available in vitro systems of CF are also described and can offer a useful alternative to using animal models. Finally, the future of CF animal model generation and their use in research is speculated upon.

PMID: 33232694 [PubMed - as supplied by publisher]

Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene.

JCI Insight. 2020 Nov 24;:

Authors: Xu J, Livraghi-Butrico A, Hou X, Rajagopalan C, Zhang J, Song J, Jiang H, Wei HG, Wang H, Bouhamdan M, Ruan J, Yang D, Qiu Y, Youming X, Barrett RP, McClellan SA, Mou H, Wu Q, Chen X, Rogers TD, Wilkinson KJ, Gilmore RC, Esther CR, Zaman K, Liang X, Sobolic M, Hazlett L, Zhang K, Frizzell RA, Gentzsch M, O'Neal WK, Grubb BR, Chen YE, Boucher RC, Sun F

Abstract
Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short life spans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of ~ 40 days and died of gastrointestinal disease, but therapeutic regimens aimed at restoring gastrointestinal transit extended median survival to ~ 80 days. Surrogate markers of exocrine pancreas disorders were found in CF rabbits with declining health. CFTR expression pattern in WT rabbit airways mimicked humans, with widespread distribution in nasal respiratory and olfactory epithelia, as well as proximal and distal lower airways. CF rabbits exhibited human CF-like abnormalities in the bioelectric properties of the upper and lower airways. No spontaneous respiratory disease was detected in young CF rabbits. However, abnormal phenotypes were observed in surviving 1 year-old CF rabbits as compared to WT littermates, which were especially evident in the nasal respiratory and olfactory epithelium. The CF rabbit model may serve as a useful tool for understanding gut and lung CF pathogenesis and for the practical development of CF therapeutics.

PMID: 33232302 [PubMed - as supplied by publisher]