Treatment with BKI-1748 after Toxoplasma gondii systemic dissemination in experimentally infected pregnant sheep improves fetal and lamb mortality and morbidity and prevents congenital infection

Abstract

Drug development for congenital toxoplasmosis is challenging since first-line therapy has a high rate of adverse effects and exhibits suboptimal efficacy. Bumped kinase inhibitors (BKIs), targeting protein kinases with small gatekeeper residues, have been found to be effective against Toxoplasma gondii. The efficacy of BKI-1748 administered later than 2 days post-infection (p.i.), a scenario that may better reflect its real-world use as a therapeutic candidate, has not been investigated in T. gondii-infected pregnant sheep. For this purpose, 19 pregnant sheep were assigned to three experimental groups. Group 1 (G1, n = 8) and group 2 (G2, n = 8) were dosed orally with 10 TgShSp1 sporulated oocysts at 90 days of gestation (dg). Animals from group 3 (G3, n = 3) were simultaneously mock dosed with phosphate-buffered solution (PBS). In G1, BKI-1748 was administered orally from day 7 p.i. (fever and increased serum IFNγ levels) onward, maintaining drug exposure for 20 days (10 doses at 15 mg/kg every 2 days). Treated animals (G1) exhibited significantly lower rectal temperatures (on days 8 and 9 p.i.), serum IFNγ levels (on day 10 p.i.), and specific IgG levels when compared with non-treated animals (G2). At delivery, significantly higher percentages of healthy lambs were found in infected/treated sheep in G1 (73.3%) and in uninfected sheep in G3 (80%) compared with infected/untreated sheep in G2 (31.3%). Concerning congenital transmission, parasite DNA was neither detected in placenta nor target tissues (brain and lungs) from the fetuses/lambs in G1(infected/treated) and G3 (uninfected). By contrast, parasite DNA was detected in all placentas and lambs from G2 (infected/untreated), except for one sheep that aborted on day 13 p.i.