An in vitro larval growth model of Dirofilaria immitis as a drug model for veterinary heartworm

Mon15  Apr05:00pm(15 mins)
Where:
Renold C2

Authors

A E Marriott1; J Furlong-Silva1; A Steven1; J Archer1; M J Taylor1; J D Turner1
1 Centre for Drugs and Diagnostics Research Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, UK

Discussion

Dirofilaria immitis and D. repens are mosquito-borne filarial parasites that cause heartworm disease in cats and dogs. Left untreated, they can cause life-threatening morbidities, including congestive heart failure and cardiopulmonary embolism. Dirofilaria species are also capable of causing zoonotic pathologies in humans.

In recent years, disease incidence has increased in USA and Europe, in tandem with geographical expansion due to spread of Aedes mosquito habitats and more favourable climatic conditions for transmission. Current prophylactic treatments rely on continuous, monthly administration of macrocyclic lactones (ML) to block larval development in client owned cats or dogs; however cases of ML resistance have been identified. Curative treatment with melarsomine can cause potentially fatal adverse reactions in dogs and there is no safe drug cure for cats. A new, alternative approach treatment is the blockade of the endosymbiont, Wolbachia, to prevent larval development or to block transmission and cure adut heartworm. However, with a heavy reliance on cat or dog in vivo models for drug testing, the evaluation of new therapies is time-consuming, laborious and expensive.

To more rapidly assess candidates with matching or improved efficacy against gold-standard ML or anti-Wolbachia treatments and to reduce the number of severe experimental procedures in cats or dogs in line with ‘3Rs’ principles in animal experimentation, we have developed an in vitro larval model utilising a canine kidney cell line co-culture system. The co-culture reproducibily supports the development and full viability of D. immitis L4 larvae for a minimum of 28 days. We demonstrate the optimisation of the larval growth culture model using molecular and morphological parameters as markers of in vitro ‘fitness’ and have validated the system as a drug model using reference ML drugs (ivermectin, moxidectin) or the anti-Wolbachia treatment, doxycycline. We are now beginning to deploy the model to scrutinise advanced anti-Wolbachia drug candidates, including repurposing opportunities and new chemical entities with narrow spectrum activity, with proven efficacy against human filarial disease, in order to identify a portfolio of alternative prophylactic and potentially curative treatments targeting veterinary heartworm. 

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