30 oct 2023 - 15:24 CET
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
Congenital toxoplasmosis in humans and in some mammalian species, such as small ruminants, is a well-known cause of abortion and foetal 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. The rates of congenital infection and foetal damage in sheep seem to mimic the situation in human toxoplasmosis more closely than those in mouse models. Ten doses of BKI-1748 given every other day orally in sheep at 15 mg/kg exhibited therapeutic plasma levels for 23 days and no systemic or pregnancy-related toxicity was observed. In sheep experimentally infected at 90 days of pregnancy with a T. gondii oocyst dose which was lethal for all foetuses, 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, higher IFNγ levels 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.