Abstract
Current efforts to eliminate the neglected tropical diseases onchocerciasis and lymphatic filariasis, caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti or Brugia spp., respectively, are hampered by lack of a short-course macrofilaricidal–adult-worm killing–treatment. Anti-wolbachial antibiotics, e.g. doxycycline, target the essential Wolbachia endosymbionts of filariae and are a safe prototype adult-worm-sterilizing and macrofilaricidal regimen, in contrast to standard treatments with ivermectin or diethylcarbamazine, which mainly target the microfilariae. However, treatment regimens of 4–5 weeks necessary for doxycycline and contraindications limit its use. Therefore, we tested the preclinical anti-Wolbachia drug candidate Corallopyronin A (CorA) for in vivo efficacy during initial and chronic filarial infections in the Litomosoides sigmodontis rodent model. CorA treatment for 14 days beginning immediately after infection cleared >90% of Wolbachia endosymbionts from filariae and prevented development into adult worms. CorA treatment of patently infected microfilaremic gerbils for 14 days with 30 mg/kg twice a day (BID) achieved a sustained reduction of >99% of Wolbachia endosymbionts from adult filariae and microfilariae, followed by complete inhibition of filarial embryogenesis resulting in clearance of microfilariae. Combined treatment of CorA and albendazole, a drug currently co-administered during mass drug administrations and previously shown to enhance efficacy of anti-Wolbachia drugs, achieved microfilarial clearance after 7 days of treatment at a lower BID dose of 10 mg/kg CorA, a Human Equivalent Dose of 1.4 mg/kg. Importantly, this combination led to a significant reduction in the adult worm burden, which has not yet been published with other anti-Wolbachia candidates tested in this model. In summary, CorA is a preclinical candidate for filariasis, which significantly reduces treatment times required to achieve sustained Wolbachia depletion, clearance of microfilariae, and inhibition of embryogenesis. In combination with albendazole, CorA is robustly macrofilaricidal after 7 days of treatment and fulfills the Target Product Profile for a macrofilaricidal drug.
Highlights
The new WHO roadmap 2030, referring to the United Nations Sustainable Development Goals, state that the Neglected Tropical Diseases onchocerciasis and lymphatic filariasis should be eliminated by 2030, at least in the majority of endemic countries [1,2]
Using the Litomosoides sigmodontis rodent model of filariasis we demonstrated that 2 weeks of Corallopyronin A (CorA) treatment clears Wolbachia endosymbionts in vivo, leading to a maintained clearance of microfilariae by inhibition of filarial embryogenesis
We have shown that Wolbachia are susceptible to CorA in vitro [28], and an in vivo 28-day CorA treatment of mice beginning one day after infection with L. sigmodontis depleted Wolbachia endosymbionts and inhibited the molting of infectious L3 into adult filariae [28]
Summary
The new WHO roadmap 2030, referring to the United Nations Sustainable Development Goals, state that the Neglected Tropical Diseases onchocerciasis and lymphatic filariasis should be eliminated by 2030, at least in the majority of endemic countries [1,2]. Onchocerciasis and lymphatic filariasis are caused by filarial nematodes and represent a great public health and economic burden for endemic countries. Current efforts to eliminate both filarial diseases are hampered by the lack of a macrofilaricidal drug, i.e. killing the adult worms that will otherwise live for 5–15 years, continuously producing new offspring, the microfilariae (MF), sustaining the transmission cycle. Current control strategies are restricted to (semi-) annual mass drug administration (MDA) with drugs that temporarily inhibit embryogenesis and lead to clearance of the MF, with the aim to interrupt the transmission of the disease. In areas endemic for onchocerciasis, MDA with ivermectin or ivermectin plus albendazole (ALB) are given for both onchocerciasis and lymphatic filariasis [3], whereas in areas outside of Africa a triple therapy with ivermectin, ALB and diethylcarbamazine is recommended by the WHO for lymphatic filariasis [4]
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