Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

Yan, Ziying; Stewart, Zoe A.; Sinn, Patrick L.; Olsen, John C.; Hu, Jim; McCray, Paul B.; Engelhardt, John F.

doi:10.1089/humc.2014.154

Cited by 67 publications

(48 citation statements)

References 147 publications

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“…Bacterial and host factors that lead to failed clearance of the infected airway are likely important for this transition, though this is difficult to test directly in murine pneumonia models, where the acute-to-chronic transition is not observed. In the following section we review what has been learned about this transition from infecting mice with agar-encapsulated P. aeruginosa, from characterizing new non-murine models of CF (such as the pig and ferret [81]), and from increasingly sophisticated analyses of patients chronically infected with this organism.…”

Section: Survival Of the Fittest: Adapted To Thrive In The Inflamed Lungmentioning

confidence: 99%

Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection

Lin

Kazmierczak²

2017

J Innate Immun

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The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

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Section: Survival Of the Fittest: Adapted To Thrive In The Inflamed Lungmentioning

confidence: 99%

Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection

Lin

Kazmierczak²

2017

J Innate Immun

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“…Firstly, the effects of roscovitine on CF models (organoïds [234], ferret [235–237] and pig [95–98, 237, 238] models of CF, P. aeruginosa infection animal models [238, 239]) should be investigated. Secondly, given the host directed antibacterial effects of roscovitine, its action on other pulmonary pathogens associated with CF, besides P. aeruginosa , [240–242], should be investigated.…”

Section: Discussionmentioning

confidence: 99%

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

et al. 2016

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(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

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“…Importantly, Croyle et al showed that gene transduction in mouse lungs with HD-AdV was maintained after a second administration conducted 28 days after the initial dosing [92]. Airway transduction with HD-AdV has also been demonstrated in larger animals, including the ferret [93] and pig [94], further supporting its potential for inhaled gene therapy applications.…”

Section: Gene Delivery Platformsmentioning

confidence: 99%

“…Of note, submucosal glands are the primary source of the airway mucus secretion in the human lungs [200] and plays critical roles in innate immunity by secreting antimicrobials [342]. A recent study also found an alternative chloride channel is present in the mouse lung that can compensate for the lack of CFTR activity [93]. …”

Section: Preclinical Modelsmentioning

confidence: 99%

Barriers to inhaled gene therapy of obstructive lung diseases: A review

Kim

Duncan

Hanes

et al. 2016

Journal of Controlled Release

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Knowledge of genetic origins of obstructive lung diseases has made inhaled gene therapy an attractive alternative to the current standards of care that are limited to managing disease symptoms. Initial lung gene therapy clinical trials occurred in the early 1990s following the discovery of the genetic defect responsible for cystic fibrosis (CF), a monogenic disorder. However, despite over two decades of intensive effort, gene therapy has yet to help patients with CF or any other obstructive lung disease. The slow progress is due in part to poor understanding of the biological barriers to inhaled gene therapy. Encouragingly, clinical trials have shown that inhaled gene therapy with various viral vectors and non-viral gene vectors is well tolerated by patients, and continued research has provided valuable lessons and resources that may lead to future success of this therapeutic strategy. In this review, we first introduce representative obstructive lung diseases and examine limitations of currently available therapeutic options. We then review key components for successful execution of inhaled gene therapy, including gene delivery systems, primary physiological barriers and strategies to overcome them, and advances in preclinical disease models with which the most promising systems may be identified for human clinical trials.

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Ferret and Pig Models of Cystic Fibrosis: Prospects and Promise for Gene Therapy

Cited by 67 publications

References 147 publications

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis

Barriers to inhaled gene therapy of obstructive lung diseases: A review

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