Macrofilaricides: An Unmet Medical Need for Filarial Diseases

Abstract

Neglected parasitic helminth diseases such as onchocerciasis and lymphatic filariasis affect an estimated 145 million people worldwide, creating a serious health burden in endemic areas such as sub-Saharan Africa and India. Although these diseases are not usually lethal, these filarial nematodes, transmitted by blood-feeding insect vectors, cause severe debilitation and cause chronic disability to infected individuals. The adult worms can reproduce from 5 to up to 14 years, releasing millions of microfilariae, juvenile worms, over an infected individual's lifetime. The current treatments for controlling human filarial infections is focused on killing microfilariae, the earliest larval stage. Currently, there is an unmet medical need for treatments consisting of a macrofilaricidal regimen, one that targets the adult stage of the parasite, to increase the rate of elimination, allow for safe use in coendemic regions of Onchocerca volvulus and Loa loa, and to provide a rapid method to resolve reinfections. Herein, recent approaches for targeting human filarial diseases are discussed, including direct acting agents to target parasitic nematodes and antibacterial approaches to target the endosymbiotic bacteria, Wolbachia.

Human filariasis—contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model

“…Microfilaricidal drugs target the progeny of filarial worms (microfilariae), which are taken up by the vector to transmit the parasite, whereas macrofilaricidal drugs target the adult stage. A significant amount of research capacities is currently focused on the development and validation of novel macrofilaricidal treatment strategies (Bakowski and McNamara 2019 ; Jacobs et al 2019 ; Taylor et al 2019 ; Hübner et al 2019a ; Ehrens et al 2020 ; Geary et al 2019 ; Hübner et al 2020 ; Hawryluk 2020 ). Since human pathogenic filariae can survive in the host for years (Geary and Mackenzie 2011 ), microfilaricidal strategies generally only block the transmission of infections temporarily and are unable to completely eliminate the parasite.…”

“…Since human pathogenic filariae can survive in the host for years (Geary and Mackenzie 2011 ), microfilaricidal strategies generally only block the transmission of infections temporarily and are unable to completely eliminate the parasite. MDA strategies based on macrofilaricidal drugs may be able to achieve elimination much quicker (Hawryluk 2020 ).…”

Zoonotic Implications of Onchocerca Species on Human Health

“…The risk of developing blindness increases with greater exposure to a high microfilariae load [148]. The results are impaired vision from corneal opacities, cataract, chorioretinal degeneration, optic atrophy, and in severe cases permanent blindness with subsequent chronic disability and reduced life expectancy [147,149].…”

“…Thus, it seems that the Onchocerca species infecting animals but found in the human ocular tissues involved adult parasites present in the conjunctiva and the cornea, as it happens in their natural hosts [30,74]. This contrasts with O. volvulus infection in humans where microfilariae are found in the ocular tissues and are responsible for the ocular damage [148,149].…”

Filarial nematode phenotypic screening cascade to identify compounds with anti-parasitic activity for drug discovery optimization

“…In areas co-endemic for loiasis and onchocerciasis, neurological adverse events consisting of coma, some of which resulted in encephalopathy, Parkinson's disease, or death, have been observed in a limited patient population treated with ivermectin, as a result of rapid depletion of circulating Loa loa microfilariae ( Holmes, 2013 ). The need for repeated drug administration, concerns about serious L. loa -related adverse events, and the possible emergence of ivermectin-resistant O. volvulus have heightened the need for compounds that exhibit adult stage selectivity (macrofilaricidal) or long-lasting sterilizing effects ( Hawryluk, 2020 ). Current efforts to control and eliminate onchocerciasis are hindered by the lack of medicines that target the adult worm stage ( Hawryluk and Scandale, 2019 ).…”