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

PLoS Neglected Tropical Diseases
Marc P HübnerA Hoerauf

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....Continue Reading

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Citations

Jul 9, 2020·PLoS Pathogens·Emma L GundersonJudy A Sakanari
Dec 8, 2020·PLoS Neglected Tropical Diseases·Andrea SchieferAchim Hoerauf
Jul 8, 2021·Trends in Parasitology·Kelly L JohnstonMark J Taylor
Feb 25, 2020·ACS Infectious Diseases·Natalie A Hawryluk
Jun 20, 2020·ACS Medicinal Chemistry Letters·Dale J Kempf, Kennan C Marsh
Oct 14, 2021·Parasitology Research·Adela NgwewondoSabine Specht

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Methods Mentioned

BETA
MDA
PCR

Software Mentioned

GraphPad
GraphPad Prism

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