In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae

Abstract

Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4–6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti- Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3–4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

“…However, previous work from our group with doxycycline showed that 4 weeks of doxycycline therapy clear Wolbachia endosymbionts and provide a macrofilaricidal efficacy in onchocerciasis and lymphatic filariasis patients [ 2 , 56 , 57 ], demonstrating that the results from the L . sigmodontis rodent model [ 27 , 58 ] are transferable to humans in this case. Furthermore, drugs currently used for human filariasis—albendazole, ivermectin and DEC—show a comparable phenotype in the L .…”

The endosymbiont Wolbachia rebounds following antibiotic treatment

“…Wolbachia titers were reduced by >95% in female worms from rifampicin treated animals at the 1-week timepoint compared to those of worms from vehicle animals. The extensive reduction of Wolbachia titers in adult worms has been previously described in other rodent studies with filarial worms, but the studies were terminated 16-18 weeks post-treatment [26,27,29,40,50], and the long-term effects of antibiotic treatment on filarial worms and their Wolbachia were not evaluated in these models.…”

“…Major efforts to identify new drugs to treat the adult stage (macrofilariae) of Onchocerca volvulus have led to the discovery of novel anti- Wolbachia compounds. These studies demonstrated that their respective anti- Wolbachia compounds significantly reduced Wolbachia titers in worms from animals treated with short courses of quinazolines and Tylosin analogs after 16–18 weeks post-first dose [ 26 , 27 , 29 , 40 , 50 ]. In addition, a one-week combination treatment of rifampicin and albendazole resulted in a greater than 99% reduction in Wolbachia levels in B .…”

“…Several studies have recently shown that short courses of 7-and 14-days of anti-Wolbachia compounds hold promise as excellent drugs to treat onchocerciasis and LF [25][26][27][28][29]. Studies by Hübner et al however, showed that suboptimal treatment regimens of doxycycline in the Litomosoides sigmodontis infection model did not lead to a sustained reduction in Wolbachia loads in worms 14-18 weeks post-treatment and that longer term studies were needed to assess permanent sterilization of female adult worms [27,29].…”

“…Several studies have recently shown that short courses of 7-and 14-days of anti-Wolbachia compounds hold promise as excellent drugs to treat onchocerciasis and LF [25][26][27][28][29]. Studies by Hübner et al however, showed that suboptimal treatment regimens of doxycycline in the Litomosoides sigmodontis infection model did not lead to a sustained reduction in Wolbachia loads in worms 14-18 weeks post-treatment and that longer term studies were needed to assess permanent sterilization of female adult worms [27,29]. Although West African cattle infected with Onchocerca ochengi are excellent hosts for long-term studies to evaluate the efficacy of antibiotics for the treatment of human onchocerciasis [30][31][32][33][34][35][36], the purpose of our study was to investigate the long-term effects of rifampicin in a rodent model of infection.…”