%0 Journal Article
%A Sánchez Sánchez, Roberto
%A Ferré Pérez, Ignacio
%A Re, Michela Tatiana
%A Ramos, Juan José
%A Regidor Cerrillo, Javier
%A Pizarro Díaz, Manuel
%A González Huecas, Marta
%A Tabanera De Lucio, Enrique
%A Benavides, Julio
%A Hemphill, Andrew
%A Hulverson, Matthew A.
%A Barrett, Lynn K.
%A Choi, Ryan
%A Whitman, Grant R.
%A Ojo, Kayode K.
%A Van Voorhis, Wesley C.
%A Ortega Mora, Luis Miguel
%T Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy
%D 2019
%@ 0066-4804
%U https://hdl.handle.net/20.500.14352/112160
%X Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 μM and trough concentrations of 0.4 μM at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.
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