Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

Guillon, Antoine; Sécher, Thomas; Dailey, Lea Ann; Vecellio, Laurent; Monte, M. De; Si‐Tahar, Mustapha; Diot, Patrice; Page, Clive; Heuzé-Vourc’h, Nathalie

doi:10.1016/j.ijpharm.2017.11.049

Cited by 35 publications

(32 citation statements)

References 114 publications

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“…In addition, drugs tend to be less potent using this method compared to an aerosol inhalation method likely due to the altered lung distribution patterns 29 . Whole-body exposure is also feasible in rodents, but the size of the inhaled particles cannot be controlled and therefore the exact quantity of drug deposited in the lungs is difficult to determine making extrapolations from rodent data to humans challenging 21 . In contrast, and because of their size, the use of large animals offers the opportunity to better study PK, in conjunction with formulation or device efficiency 28 .…”

Section: Discussionmentioning

confidence: 99%

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Mora

Detalle

Gallup

et al. 2018

mAbs

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Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory disease in infants and young children worldwide. Currently, treatment is supportive and no vaccines are available. The use of newborn lambs to model hRSV infection in human infants may provide a valuable tool to assess safety and efficacy of new antiviral drugs and vaccines. ALX-0171 is a trivalent Nanobody targeting the hRSV fusion (F) protein and its therapeutic potential was evaluated in newborn lambs infected with a human strain of RSV followed by daily ALX-0171 nebulization for 3 or 5 consecutive days.Colostrum-deprived newborn lambs were infected with hRSV-M37 before being treated by daily nebulization with either ALX-0171 or placebo. Two different treatment regimens were examined: day 1–5 or day 3–5 post-infection. Lambs were monitored daily for general well-being and clinical parameters. Respiratory tissues and bronchoalveolar lavage fluid were collected at day 6 post-inoculation for the quantification of viral lesions, lung viral titers, viral antigen and lung histopathology.Administration by inhalation of ALX-0171 was well-tolerated in these hRSV-infected newborn lambs. Robust antiviral effects and positive effects on hRSV-induced lung lesions and reduction in symptoms of illness were noted. These effects were still apparent when treatment start was delayed and coincided with peak viral loads (day 3 post-infection) and at a time point when signs of RSV disease were apparent. The latter design is expected to have high translational value for planned clinical trials. These results are indicative of the therapeutic potential of ALX-0171 in infants.

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Section: Discussionmentioning

confidence: 99%

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Mora

Detalle

Gallup

et al. 2018

mAbs

View full text Add to dashboard Cite

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“…The animal model used herein has a high translational potential for clinical applications; ventilator, circuit components, ventilator settings, and the endotracheal suctioning process were all identical with those used for patients under mechanical ventilation. The overall design of this experiment allows us to be confident in the potential translation into the clinics (27).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Pseudomonas aeruginosa Biofilm Present in Endotracheal Tubes by Poly- l -Lysine

Guillon

Fouquenet

Morello

et al. 2018

Antimicrob Agents Chemother

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The endotracheal tube (ETT) is an essential interface between the patient and ventilator in mechanically ventilated patients. However, a microbial biofilm is formed gradually on this tube and is associated with the development of ventilator-associated pneumonia. The bacteria present in the biofilm are more resistant to antibiotics, and current medical practices do not make it possible to eliminate. is one of the leading pathogens that cause biofilm infections and ventilator-associated pneumonia. Poly-l-lysine (pLK) is a cationic polypeptide possessing antibacterial properties and mucolytic activity by compacting DNA. Here, we explored the antibiofilm activity of pLK to treat biofilms on ETTs while taking into consideration the necessary constraints for clinical translation in our experimental designs. First, we showed that pLK eradicates a biofilm formed on 96-well microplates. We further demonstrated that pLK alters bacterial membrane integrity, as revealed by scanning electron microscopy, and eventually eradicates biofilm formed either by reference or clinical strains of biofilms generated on ETTs. Second, we collected the ETT from patients with ventilator-associated pneumonia. We observed that a single dose of pLK is able to immediately disrupt the biofilm structure and kills more than 90% of bacteria present in the biofilm. Additionally, we did not observe any lung tolerance issue when the pLK solution was instilled into the ETT of ventilated pigs, an animal model particularly relevant to mimic invasive mechanical ventilation in humans. In conclusion, pLK appears as an innovative antibiofilm molecule, which could be applied in the ETT of mechanically ventilated patients.

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“…The problem of experimental variability can be easily overcome while studying small animals by increasing the sample size, whereas it can hardly be in larger species due to technical and financial concerns. A number of excellent reviews have highlighted interspecies anatomical and physiological differences to help in the selection of appropriate animal models and ensure successful transposition in the clinics [12–16]. Indeed, a major strength of mouse models is to be able to promptly test scientific hypothesis in proof-of-concept studies, whereas the investments in personnel, equipment and consumables to develop advanced animal models can be prohibitive in early stage projects.…”

Section: Classical Animal Models Of Sepsis/septic Shock: Strengths Anmentioning

confidence: 99%

Preclinical septic shock research: why we need an animal ICU

Guillon¹,

Preau²,

Aboab³

et al. 2019

Ann. Intensive Care

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Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using—in case of rats and mice—miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.

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Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

Cited by 35 publications

References 114 publications

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

Treatment of Pseudomonas aeruginosa Biofilm Present in Endotracheal Tubes by Poly- l -Lysine

Preclinical septic shock research: why we need an animal ICU

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