Pathophysiologic evaluation of the transgenic CFTR “gut-corrected” porcine model of cystic fibrosis

Ballard, Stephen T.; Evans, Jessica W.; Drag, Holly S.; Schuler, Michele A.

doi:10.1152/ajplung.00242.2016

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…In 3-wk-old CF pigs, airway size reduction predominantly affected the proximally measured airways. A similar pattern was previously observed in newborn CF pigs (2) and in limited studies of older CF pigs (3). Developmental defects are also present in airways of CF mice and rats (4,14,30).…”

Section: Airways Are Small In Three-week-old Cf Pigssupporting

confidence: 84%

Postnatal airway growth in cystic fibrosis piglets

Adam

Alaiwa

Bouzek

et al. 2017

Journal of Applied Physiology

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Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known about postnatal CF airway growth, largely because such studies are limited in humans. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in 3-wk-old non-CF and CF pigs. We found that 3-wk-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis. This CT scan-based study of airway morphometry in the cystic fibrosis (CF) postnatal period is unique, as analogous studies in humans are greatly limited for ethical and technical reasons. Findings such as reduced airway lumen area and irregular caliber suggest that airway growth and development are CF transmembrane conductance regulator-dependent and that airway growth defects may contribute to CF lung disease pathogenesis.

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Section: Airways Are Small In Three-week-old Cf Pigssupporting

confidence: 84%

Postnatal airway growth in cystic fibrosis piglets

Adam

Alaiwa

Bouzek

et al. 2017

Journal of Applied Physiology

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“…For these reasons, second-generation gut-corrected CFTR-KO ferrets 63 and pigs 88 have been generated, which express CFTR under the direction of the intestinal fatty acid-binding protein (FABPI) promoter. Although the gutcorrected CF pig model has shown some protection from meconium ileus, 88,89 the similar model in ferret did not increase the ease of rearing despite protection from meconium ileus (unpublished). For these reasons, a thirdgeneration CF ferret model was engineered to harbor a CFTR-G551D mutation (CFTR G551D ) that is responsive to the CFTR modulator drug VX-770.…”

Section: Animal Models Of Cfmentioning

confidence: 99%

Viral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease

2020

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After more than two decades since clinical trials tested the first use of recombinant adeno-associated virus (rAAV) to treat cystic fibrosis (CF) lung disease, gene therapy for this disorder has undergone a tremendous resurgence. Fueling this enthusiasm has been an enhanced understanding of rAAV transduction biology and cellular processes that limit transduction of airway epithelia, the development of new rAAV serotypes and other vector systems with high-level tropism for airway epithelial cells, an improved understanding of CF lung pathogenesis and the cellular targets for gene therapy, and the development of new animal models that reproduce the human CF disease phenotype. These advances have created a preclinical path for both assessing the efficacy of gene therapies in the CF lung and interrogating the target cell types in the lung required for complementation of the CF disease state. Lessons learned from early gene therapy attempts with rAAV in the CF lung have guided thinking for the testing of next-generation vector systems. Although unknown questions still remain regarding the cellular targets in the lung that are required or sufficient to complement CF lung disease, the field is now well positioned to tackle these challenges. This review will highlight the role that nextgeneration CF animal models are playing in the preclinical development of gene therapies for CF lung disease and the knowledge gaps in disease pathophysiology that these models are attempting to fill.

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“…95 Subsequent studies in cloned gut-corrected pigs found elevated neonatal mortalities, prompted by systemic edema, hepatic abnormalities, and chronic hypoproteinemia immediately after birth. 96 Scientists have developed ferret CFTR -/knockout models that also express CFTR under FABP promoter, reducing the rates of MI from 75% to nonexistent. Their size and faster gestation period provide some advantages compared to pigs, and they develop vas deferens deficiencies like humans and unlike pigs.…”

Section: Delivering Rna Therapies To the Cf Lung Is Challengingmentioning

confidence: 99%

“…102 As described, there have been significant advances made in the development of CF animal models, which have been reviewed in detail. [93][94][95][96][97][98][99][100][101][102] There have been advances in the last decade that address the first three steps in the drug delivery process of RNA therapies for CF. First, there have been reports that densely coating nanoparticles with polyethylene glycol (PEG) seems to improve transport past different mucosal surfaces in humans.…”

Section: Delivering Rna Therapies To the Cf Lung Is Challengingmentioning

confidence: 99%

Treating Cystic Fibrosis with mRNA and CRISPR

et al. 2020

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Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA-and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. In this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA-or CRISPR-based drugs to treat CF successfully in patients.

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Pathophysiologic evaluation of the transgenic CFTR “gut-corrected” porcine model of cystic fibrosis

Cited by 11 publications

References 32 publications

Postnatal airway growth in cystic fibrosis piglets

Postnatal airway growth in cystic fibrosis piglets

Viral Vectors, Animal Models, and Cellular Targets for Gene Therapy of Cystic Fibrosis Lung Disease

Treating Cystic Fibrosis with mRNA and CRISPR

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