Adoption of a mouse model of veterinary filariasis for preclinical drug testing

Why did we fund this project?

This award aims to refine the study of heartworm treatments using a mouse model instead of cats and dogs.

Heartworm is a parasitic disease caused by a filarial worm that predominantly effects cats and dogs. The worms reside in the heart or adjacent large blood vessels and left untreated, cause life-threatening disease. Current treatment options however can be also problematic as they induce rapid death of the worms which can be fatal to the infected animal. New therapeutics are typically tested in cats and dogs infected with heartworm. The studies can last up to a year with the animals experiencing a range of symptoms from reduced activity and labored breathing to cardiopulmonary embolism as a result of the filarial infection. With NC3Rs funding, Dr Joseph Turner has previously developed a short-term mouse model of heartworm that mimics the early stages of infection to avoid the use of cats and dogs. The parasites are propagated under the skin that combined with the short length of the experiment (up to two weeks) reduces the nature of the suffering caused when compared with the standard in vivo studies.

Joe will transfer the mouse model to two laboratories who have published over 50% of the papers on heartworm drug development in the last three years. The model will be validated by comparing parasitic yields and reference drug responses to results from Joe’s laboratory. The protocols and validation will be publicised on the Filariasis Research Resource Repository website and at conferences to encourage further uptake in the research community.

Heartworm is a potentially life-threatening infectious disease of companion animals and the cause of zoonotic pathologies in humans. Heartworm drug research and development has been reinvigorated by the identification of drug-resistant isolates of the causative agent, Dirofilaria. Current in vitro assays to assess drug response are poorly predictive of in vivo efficacy, requiring a reliance on cat and dog testing. We estimate that at least 221 experimentally reared cats and dogs are utilised per annum in heartworm related research. We have established an immunodeficient mouse model of D. immitis subcutaneous infection with reproducible performance across multiple experiments over the first 14-18 days of larval development. We have validated reference treatment responses in vivo. Heartworms propagated in mice are physiologically superior to in vitro cultured larvae and can also be utilized ex vivo in drug response titrations for more accurate pharmacodynamic assessments.

In this project, we will transfer the new larval heartworm mouse model to two major end-user organisations who, combined, contributed 52% of published heartworm drug R&D procedures over the past 3 years. Variability in parasitic yields and reference drug responses in the model will be appraised in partnership with end-user laboratories. We estimate that future adoption of the new model within both end-user organisations has the potential to reduce the number of laboratory-reared cat and dog experiments by 57 per annum and thus offer a refinement by reducing total procedures causing severe harm in these specially protected species. Working with our end-user partners we will disseminate further knowledge transfer to other heartworm R&D stakeholders, including major veterinary healthcare companies, via publication of protocols and inter-laboratory performance via the Filariasis Research Resource Repository website and holding a workshop at The American Heartworm Society Triannual meeting.

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Skills and Knowledge Transfer grant

Status

Active

Institution

Liverpool School of Tropical Medicine

Grant reference number

NC/W000970/1

Award date

Sep 2021 - Dec 2022

Grant amount

£75,686