Animal and Cell Culture Models for Cystic Fibrosis

McCarron, Alexandra; Parsons, David; Donnelley, Martin

doi:10.1016/j.ajpath.2020.10.017

Cited by 54 publications

(39 citation statements)

References 112 publications

(184 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the present study was not designed to assess the effects of altered airway mucus rheology on MP penetration or LV-MP transduction levels. Future imaging studies should test MP behaviour in an appropriate CF model 32 , along with alternative MP that are capable of penetrating mucus 33 , which could be assessed to verify whether they further improve transduction levels. Finally, all these studies were performed only in the trachea.…”

Section: Discussionmentioning

confidence: 99%

Improved in-vivo airway gene transfer via magnetic-guidance, with protocol development informed by synchrotron imaging

Donnelley

Cmielewski

Morgan

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Gene vectors to treat cystic fibrosis lung disease should be targeted to the conducting airways, as peripheral lung transduction does not offer therapeutic benefit. Viral transduction efficiency is directly related to the vector residence time. However, delivered fluids such as gene vectors naturally spread to the alveoli during inspiration, and therapeutic particles of any form are rapidly cleared via mucociliary transit. Extending gene vector residence time within the conducting airways is important, but hard to achieve. Gene vector conjugated magnetic particles that can be guided to the conducting airway surfaces could improve regional targeting. Due to the challenges of in-vivo visualisation, the behaviour of such small magnetic particles on the airway surface in the presence of an applied magnetic field is poorly understood. The aim of this study was to use synchrotron imaging to visualise the in-vivo motion of a range of magnetic particles in the trachea of anaesthetised rats to examine the dynamics and patterns of individual and bulk particle behaviour in-vivo. We also then assessed whether lentiviral-magnetic particle delivery in the presence of a magnetic field increases transduction efficiency in the rat trachea. Synchrotron X-ray imaging revealed the behaviour of magnetic particles in stationary and moving magnetic fields, both in-vitro and in-vivo. Particles could not easily be dragged along the live airway surface with the magnet, but during delivery deposition was focussed within the field of view where the magnetic field was the strongest. Transduction efficiency was also improved six-fold when the lentiviral-magnetic particles were delivered in the presence of a magnetic field. Together these results show that lentiviral-magnetic particles and magnetic fields may be a valuable approach for improving gene vector targeting and increasing transduction levels in the conducting airways in-vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Improved in-vivo airway gene transfer via magnetic-guidance, with protocol development informed by synchrotron imaging

Donnelley

Cmielewski

Morgan

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Future progress in CF research requires, inter alia, appropriate cellular and animal models. In vivo models (i.e., mice, pigs, and ferrets) are particularly useful to explore the pathophysiology of CF and therapeutic strategies [ 127 ]. Nevertheless, their use in research has many limitations and disadvantages [ 127 ].…”

Section: Discussionmentioning

confidence: 99%

“…In vivo models (i.e., mice, pigs, and ferrets) are particularly useful to explore the pathophysiology of CF and therapeutic strategies [ 127 ]. Nevertheless, their use in research has many limitations and disadvantages [ 127 ]. CF murine models fail to spontaneously develop lung disease, as well as bacterial infections, due to their short life span [ 128 ].…”

Section: Discussionmentioning

confidence: 99%

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

et al. 2020

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

show abstract

“…Since the identification of the CFTR gene, numerous animal models have been developed and widely reviewed (Grubb and Boucher, 1999;Wilke et al, 2011;Lavelle et al, 2016;Rosen et al, 2018;Semaniakou et al, 2018;McCarron et al, 2021). The conservation of this gene in mammals has made it possible to generate KO models from many different species, including mouse (Snouwaert et al, 1992;Colledge et al, 1995;Hasty et al, 1995;Rozmahel et al, 1996;van Heeckeren et al, 2004), rat (Tuggle et al, 2014;Dreano et al, 2019), rabbit (Xu et al, 2021), ferret (Sun et al, 2008;Sun et al, 2010), sheep (Fan et al, 2018) and pig (Meyerholz et al, 2010).…”

Section: Cftr Knock-out Animal Models Of Cfmentioning

confidence: 99%

On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis

et al. 2021

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a severe genetic disease for which curative treatment is still lacking. Next generation biotechnologies and more efficient cell-based and in vivo disease models are accelerating the development of novel therapies for CF. Gene editing tools, like CRISPR-based systems, can be used to make targeted modifications in the genome, allowing to correct mutations directly in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Alternatively, with these tools more relevant disease models can be generated, which in turn will be invaluable to evaluate novel gene editing-based therapies for CF. This critical review offers a comprehensive description of currently available tools for genome editing, and the cell and animal models which are available to evaluate them. Next, we will give an extensive overview of proof-of-concept applications of gene editing in the field of CF. Finally, we will touch upon the challenges that need to be addressed before these proof-of-concept studies can be translated towards a therapy for people with CF.

show abstract

Animal and Cell Culture Models for Cystic Fibrosis

Cited by 54 publications

References 112 publications

Improved in-vivo airway gene transfer via magnetic-guidance, with protocol development informed by synchrotron imaging

Improved in-vivo airway gene transfer via magnetic-guidance, with protocol development informed by synchrotron imaging

The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis

Contact Info

Product

Resources

About