Around 40 million people in low-income countries are living with permanent, disfiguring limb swelling caused by lymphatic filariasis, a parasitic infection spread by mosquitoes, and no drug can reverse the damage. Current mass drug administration programmes stop the parasite from spreading but do not kill the adult worms lodged in the lymphatic system, nor do they treat the chronic swelling that already exists. This leaves a generation with a stigmatising disability that severely limits quality of life and increases the risk of mental illness. The researchers have identified a specific inflammatory pathway—the 5-lipoxygenase enzyme pathway—that drives lymphatic damage in mice, and an existing asthma drug called zileuton can block it and even reverse established disease. But no one has yet checked whether the same pathway is active in human patients. This feasibility study will take blood samples from people with mild-to-moderate filarial lymphoedema in eastern Nepal and compare them with healthy volunteers, using a sensitive method to measure inflammatory lipids that degrade rapidly after sampling. If the 5-lipoxygenase pathway is confirmed in humans, it would provide the evidence needed to launch a clinical trial of zileuton as a treatment for filarial lymphoedema—potentially offering the first therapy that can reduce existing swelling and disability, rather than just preventing new infections.
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Lymphoedema is a chronic progressive swelling of limbs caused by genetic abnormalities, or damage conferring irreparable malfunctioning lymphatics. An estimated 250 million individuals worldwide suffer lymphoedema. Of these, forty million people in Low-and-Middle-Income Countries suffer disabling and stigmatising lymphoedema morbidities invoked by lymphatic filariasis (LF); a major skin-related neglected tropical disease caused by parasitic worms and spread by mosquitoes. LF is the single largest cause of secondary lymphoedema worldwide and a major cause of global disability. The spread of LF to uninfected individuals (currently 660 million still at risk) can be prevented by annual mass drug administrations with anti-filarial drugs to whole communities where the parasites are present. These drugs work to rapidly but temporarily remove microscopic larvae (microfilariae) from the blood to prevent spread by mosquitoes. But these drugs do not cure infected individuals of adult parasites in the lymphatics, nor do they alleviate pre-existing lymphoedema. This means that even if global LF elimination is achieved in the future, a generation of people will be left with a permanent stigmatizing disability, hampering quality of life and risking development of mental illnesses. Emerging evidence links persistent 'low grade' inflammation as a contributing factor in the initiation and progression of secondary lymphoedemas, including upper arm lymphoedema following breast cancer surgery. In our current basic research programme, ‘Filariasis Lipids in Pathogenesis; FLiP’, we have established a sensitive method to measure multiple inflammatory lipids which are produced by particular enzymes as part of tissue inflammation. Using a mouse model of filariasis, we have identified >40 lipid inflammatory mediators that are highly upregulated in LF diseased lymphatic tissues. Targeting lipids produced by one particular enzymatic pathway (the 5-lipoxygenase pathway) using a registered anti-inflammatory drug, zileuton, which is often prescribed for asthma, we can significantly reduce lymphatic disease and associated white blood cell recruitments which we have previously shown are important in the initiation of lymphatic disease. Excitingly, we can also demonstrate that zileuton reduces pre-established lymphatic disease. However, we currently lack knowledge of the inflammatory lipids produced in filariasis lymphoedema patients, and in particular whether the druggable 5-lipoxygenase pathway we have identified in our mouse model is readily associated with disease in humans. This is because the correct processing to preserve rapidly degrading inflammatory lipids after human sampling has never before been undertaken in filariasis. In addition, a sufficiently accurate technique has not yet been applied to filariasis clinical samples to measure and discriminate the presence of different types of inflammatory lipid. In this MRC gap project, we will validate whether the 5-lipoxygenase druggable pathway is evident in a pilot sample of mild to moderate filarial lymphoedema patients via comparisons to healthy endemic volunteers in LF endemic Eastern Nepal, where a mass drug administration elimination programme is ongoing. We will sample the blood plasma for circulating levels of lipids, and also inflammatory lipids and 5-LOX enzyme levels produced in circulating white blood cells. We will rapidly freeze, ship and extract lipids present in these samples before measuring levels using our established highly accurate methods. This feasibility pilot data will be fundamental in the decision for funding future intervention treatment trials using zileuton to treat LF morbidity, by confirmation of target 5-lipoxygenase enzyme activity associated with clinical pathology. Simultaneously, this gap project will provide critical information necessary to inform cost-effective future clinical trial design.
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