Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.
German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
PLoS Negl Trop Dis. 2020 Dec 7;14(12):e0008930. doi: 10.1371/journal.pntd.0008930. eCollection 2020 Dec.
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.
目前，消灭由旋毛形线虫引起的被忽视热带病（盘尾丝虫病）和由班氏丝虫或布鲁氏丝虫引起的淋巴丝虫病的努力受到缺乏短期杀成虫（macrofilaricidal-adult-worm killing）药物的阻碍。抗沃尔巴克氏体抗生素，如多西环素，针对丝虫的必需内共生体沃尔巴克氏体，是一种安全的成虫绝育和杀成虫方案，与伊维菌素或乙胺嗪的标准治疗方法形成对比，这些方法主要针对微丝蚴。然而，多西环素治疗需要 4-5 周，且存在禁忌症，限制了其使用。因此，我们在利什曼原虫（Litomosoides sigmodontis）啮齿动物模型中，针对初始和慢性丝虫感染，测试了珊瑚酮 A（Corallopyronin A，CorA）这一临床前抗沃尔巴克氏体候选药物的疗效。在感染后立即开始的 14 天 CorA 治疗中，清除了 90%以上的丝虫内共生体沃尔巴克氏体，并阻止了其发育成成虫。用 30mg/kg 双日剂量（BID）的 CorA 治疗已感染的微丝蚴血症沙鼠 14 天，可使成虫和微丝蚴中的内共生体沃尔巴克氏体持续减少 >99%，随后完全抑制丝虫胚胎发生，导致微丝蚴清除。CorA 与阿苯达唑联合治疗，阿苯达唑是目前大规模药物治疗中联合使用的药物，先前已被证明可增强抗沃尔巴克氏体药物的疗效，在 7 天的治疗中，使用 CorA 10mg/kg BID 剂量，即 1.4mg/kg 的人体等效剂量，可实现微丝蚴清除。重要的是，与该模型中测试的其他抗沃尔巴克氏体候选药物相比，这种联合治疗可显著降低实现持续沃尔巴克氏体耗竭、微丝蚴清除和胚胎发生抑制所需的治疗时间。总之，CorA 是一种有前景的丝虫病临床前候选药物，可显著缩短治疗时间，实现持续的沃尔巴克氏体耗竭、微丝蚴清除和胚胎发生抑制。与阿苯达唑联合治疗，CorA 在 7 天的治疗后即可有效杀灭成虫，满足杀成虫药物的目标产品概况。
