Sequential targeting of CFTR by BAC vectors generates a novel pig model of cystic fibrosis

Klymiuk, Nikolai; Mundhenk, Lars; Kraehe, Katrin; Wuensch, A.; Plog, Stephanie; Emrich, Daniela; Langenmayer, Martin C.; Stehr, Maximilian; Holzinger, Andreas; Kröner, C.; Richter, Anne; Kessler, Benedikt M.; Kurome, Mayuko; Eddicks, Matthias; Nagashima, Hiroshi; Heinritzi, K.; Gruber, Achim D.; Wolf, Eckhard

doi:10.1007/s00109-011-0839-y

Cited by 87 publications

(91 citation statements)

References 32 publications

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“…However, the in vivo validation of these results was hampered by the fact that Cftr-deficient mice do not reproduce the basic CF ion transport defect in the airways, probably due to expression of alternative Cl -channels, and do not develop CF-like lung disease [21]. This limitation led to the generation of mice with airway-specific overexpression of ENaC (bENaC-Tg) to mimic enhanced ENaC activity [17,22] and, more recently, the generation of CFTR-deficient pigs and ferrets [23][24][25] to test the in vivo consequences of imbalanced ion/ fluid secretion and absorption across CF airways. A series of studies in bENaC-Tg mice validated the concept that ASL depletion with hyperconcentrated mucus impairs mucociliary clearance, causes CF-like mucus plugging and sets the stage for chronic airway inflammation and bacterial infection [22].…”

Section: Airway Surface Dehydration: a Key Disease Mechanism In Cf Lumentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Section: Airway Surface Dehydration: a Key Disease Mechanism In Cf Lumentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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“…Under these conditions, pigs are more likely to represent what happens in humans. In addition, CF pig models have been generated recently and their phenotyping and clinical features have been evaluated (33)(34)(35)(36)(37)(38)(39)(40), which may be useful for gene correction studies of CF.…”

Section: Discussionmentioning

confidence: 99%

Airway Deposition of Nebulized Gene Delivery Nanocomplexes Monitored by Radioimaging Agents

Manunta

McAnulty²,

McDowell³

et al. 2013

Am J Respir Cell Mol Biol

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“…While histological examination of newborn CF pigs revealed apparently normal lung tissue , the trachea had a triangular rather than a circular shape and the cartilage appeared thicker and more discontinuous than in wild-type samples Klymiuk, Mundhenk, et al 2012). This was confirmed in human CF infants Diwakar et al 2015).…”

Section: Pig Models Of Cf Provide Important Insights Into Early Diseamentioning

confidence: 99%

Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies

et al. 2015

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Despite enormous advances in translational biomedical research, there remains a growing demand for improved animal models of human disease. This is particularly true for diseases where rodent models do not reflect the human disease phenotype. Compared to rodents, pig anatomy and physiology are more similar to humans in cardiovascular, immune, respiratory, skeletal muscle, and metabolic systems. Importantly, efficient and precise techniques for genetic engineering of pigs are now available, facilitating the creation of tailored large animal models that mimic human disease mechanisms at the molecular level. In this article, the benefits of genetically engineered pigs for basic and translational research are exemplified by a novel pig model of Duchenne muscular dystrophy and by porcine models of cystic fibrosis. Particular emphasis is given to potential advantages of using these models for efficacy and safety testing of targeted therapies, such as exon skipping and gene editing, for example, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system. In general, genetically tailored pig models have the potential to bridge the gap between proof-of-concept studies in rodents and clinical trials in patients, thus supporting translational medicine.Keywords pig, disease model, Duchenne muscular dystrophy, cystic fibrosis, exon skipping, genome editing, CRISPR/Cas Genetically Engineered Pig Models of Human Monogenic DiseasesRare monogenic diseases are an attractive market for the pharmaceutical industry, since they provide-once the underlying mutation is identified-validated targets for drug development (Brinkman et al. 2006) or genetic treatment approaches (O'Connor and Crystal 2006). Development of drugs for these orphan diseases frequently has higher success rates and shorter times to approval and may-in spite of much smaller target patient populations-generate potential lifetime revenues comparable to nonorphan drugs (Fagnan et al. 2014). Currently the molecular etiology for more than half of the estimated 7,000 rare monogenic human diseases is known, and marked acceleration of disease gene discovery is expected from the dramatic improvements in DNA-sequencing technologies and associated analyses (Boycott et al. 2013). Model organisms are required to dissect the biological consequences of a particular mutation and to provide proof of concept for therapeutic intervention. The mouse is the most widely used model organism in mammalian genetics, and powerful platforms/networks for large-scale systematic mutagenesis and standardized phenotyping have been established (Bradley et al. 2012;Infrafrontier Consortium 2015). However, mutant mouse models do not always reflect the phenotypes of the corresponding human genetic diseases.Moreover, translation of findings in mouse models into clinical studies and applications may be difficult. Thus, large animal models mimicking human anatomy and physiology more closely are additionally needed. In this respect, the pig as a monogastri...

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Sequential targeting of CFTR by BAC vectors generates a novel pig model of cystic fibrosis

Cited by 87 publications

References 32 publications

CFTR: cystic fibrosis and beyond

CFTR: cystic fibrosis and beyond

Airway Deposition of Nebulized Gene Delivery Nanocomplexes Monitored by Radioimaging Agents

Tailored Pig Models for Preclinical Efficacy and Safety Testing of Targeted Therapies

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