An Early Treatment With BKI-1748 Exhibits Full Protection Against Abortion and Congenital Infection in Sheep Experimentally Infected With Toxoplasma gondii
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2023
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Oxford University Press
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Roberto Sánchez-Sánchez, Dennis Imhof, Yanina P Hecker, Ignacio Ferre, Michela Re, Javier Moreno-Gonzalo, Javier Blanco-Murcia, Elena Mejías-López, Matthew A Hulverson, Ryan Choi, Samuel L M Arnold, Kayode K Ojo, Lynn K Barrett, Andrew Hemphill, Wesley C Van Voorhis, Luis Miguel Ortega-Mora, An Early Treatment With BKI-1748 Exhibits Full Protection Against Abortion and Congenital Infection in Sheep Experimentally Infected With Toxoplasma gondii, The Journal of Infectious Diseases, Volume 229, Issue 2, 15 February 2024, Pages 558–566, https://doi.org/10.1093/infdis/jiad470
Abstract
Congenital toxoplasmosis in humans and in other mammalian species, such as small ruminants, is a well-known cause of abortion and fetal malformations. The calcium-dependent protein kinase 1 (CDPK1) inhibitor BKI-1748 has shown a promising safety profile for its use in humans and a good efficacy against Toxoplasma gondii infection in vitro and in mouse models. Ten doses of BKI-1748 given every other day orally in sheep at 15 mg/kg did not show systemic or pregnancy-related toxicity. In sheep experimentally infected at 90 days of pregnancy with 1000 TgShSp1 oocysts, the BKI-1748 treatment administered from 48 hours after infection led to complete protection against abortion and congenital infection. In addition, compared to infected/untreated sheep, treated sheep showed a drastically lower rectal temperature increase and none showed IgG seroconversion throughout the study. In conclusion, BKI-1748 treatment in pregnant sheep starting at 48 hours after infection was fully effective against congenital toxoplasmosis.