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

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Parasitology

Abstract

Heartworm is a potentially life-threatening infectious disease of cats, dogs and ferret companion animals and also can cause damage to the eyes and lungs of people who are accidentally infected. Heartworm is a global veterinary problem and is spreading across America and Europe due to climate change. As much as 400 million dollars are spent every year on treatments to stop heartworm infections in pets. Because of the emergence of drug resistant parasites, we need to develop and test new drug therapies. Drug testing is done on laboratory bred cats or dogs experimentally infected with heartworm. We estimate that at least 221 cats and dogs are utilised for this purpose yearly. These are mainly long-term experiments with a risk of severe harm occurring due to chronic worm infections of the heart and lungs.
We have established a new mouse model of heartworm. This model mimics the early stages of infections in cats and dogs with microscopic larvae growing under the skin, before they migrate to the heart to cause disease. We have tested current heartworm drugs in this mouse model and also after removing the developing parasites and incubating them outside of the body. We have determined that these models can be used to successfully evaluate new drugs.
In this project, we will transfer the new larval heartworm mouse model to two major end-user organisations who have been involved in approximately half of all published research on heartworm drugs over the last three years. With our end-user partners we will share protocols and undertake experiments to evaluate how well the model works in these establishments as a way of measuring anti-heartworm drug responses.
We will then share our protocols and findings by free to access publication, by posting methods and results on a website accessed by many heartworm researchers worldwide and by running a workshop at a major heartworm meeting attended by major stakeholders such as academics, practitioners and representatives of the animal healthcare industry.
We estimate that the future adoption of the new mouse model of heartworm to test drugs could reduce up to two-thirds of the cats and dogs currently used and thus also reduce the total numbers of procedures causing suffering in these specially-protected species.

Technical Summary

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.

Publications

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