Diversifying animal models: the use of hispid cotton rats (<i>Sigmodon hispidus</i>) in infectious diseases

Niewiesk, Stefan; Prince, Gregory A.

doi:10.1258/002367702320389026

Cited by 101 publications

(110 citation statements)

References 72 publications

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“…To determine the druggability of targeting the de novo pyrimidine pathway for antiviral efficacy, the RSV cotton rat model was chosen (23). Prior to assessment, in vivo PK was established for 6b via subcutaneous and oral routes at 10 mg∕kg to enable study design for efficacy studies.…”

Section: Resultsmentioning

confidence: 99%

“…There are a number of animal models available for studying RSV, including primates, cows, cotton rats, and mice, each with its own set of advantages and disadvantages (52). In terms of rodents, we chose to use the cotton rat, because they have been shown to be at least 50-fold, and as much as 1,000-fold, more permissive than mouse strains for RSV (23), with the virus replicating in the nasal epithelium and bronchiolar epithelium of the animal (53). Because the in vitro antiviral effect of CAD phenocopies that of DHODH (the rate-limiting step), we chose to profile DHODH inhibition in the cotton rat model.…”

Section: Discussionmentioning

confidence: 99%

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Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Although semi-permissive to hRSV infection, cotton rat studies have proven useful as both RSVIg (RespiGam®) and palivizumab (Synagis®) were advanced to clinical trials solely based on cotton rat data 11 . However, as the intended route of administration for ALX-0171 is by inhalation, adequate drug deposition in the lung is a prerequisite for efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Different animal models for RSV infection, including non-human primates, calves, lambs, mice, guinea pigs, ferrets, hamsters and cotton rats have been described 9 10 The cotton rat (Sigmodon hispidus) RSV infection model has been successfully used in the development of both RSV-IgIV (RespiGam®, MedImmune) and palivizumab and findings in the cotton rat for those agents translated well to the clinical setting 11 12 The cotton rat model also serves as the primary model for the determination of vaccine safety because these animals develop vaccine-associated worsening of pulmonary disease upon subsequent infection with RSV that reflects what is seen in humans and non-human primates 13 .…”

Section: Introductionmentioning

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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“…12 Cotton rats are considered a more relevant animal model than mice for the efficacy and safety of RSV vaccines and drugs. 13,14 Here, we investigated the immunogenicity, efficacy, and safety of F VLP, G VLP, and FG VLP in cotton rats. Mixed FG VLP and F VLP vaccines were effective in conferring protection and in preventing vaccine-enhanced disease of pulmonary inflammation after RSV challenge.…”

Section: Introductionmentioning

confidence: 99%

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

Hwang

Kim

Lee

et al. 2017

Human Vaccines & Immunotherapeutics

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Vaccine-enhanced disease has been a major obstacle in developing a safe vaccine against respiratory syncytial virus (RSV). This study demonstrates the immunogenicity, efficacy, and safety of virus-like particle (VLP) vaccines containing RSV F (F VLP), G (G VLP), or F and G proteins (FG VLP) in cotton rats. RSV specific antibodies were effectively induced by vaccination of cotton rats with F VLP or FG VLP vaccines. After challenge, lung RSV clearance was observed with RSV F, G, FG VLP, and formalin inactivated RSV (FI-RSV) vaccines. Upon RSV infection, cotton rats with RSV VLP vaccines were protected against airway hyperresponsiveness and weight loss, which are different from FI-RSV vaccination exhibiting vaccine-enhanced disease of airway obstruction, weight loss, and severe histopathology with eosinophilia and mucus production. FG VLP and F VLP vaccines did not cause pulmonary inflammation whereas G VLP induced moderate lung inflammation with eosinophilia and mucus production. In particular, F VLP and FG VLP vaccines were found to be effective in inducing antibody secreting cell responses in bone marrow and lymphoid organs as well as avoiding the induction of T helper type 2 cytokines. These results provide further evidence to develop a safe RSV vaccine based on VLP platforms.

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Diversifying animal models: the use of hispid cotton rats (Sigmodon hispidus) in infectious diseases

Cited by 101 publications

References 72 publications

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

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

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

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