An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii

Autores
Sánchez Sánchez, Roberto; Imhof, Dennis; Hecker, Yanina Paola; Ferre, Ignacio; Re, Michela; Moreno Gonzalo, Javier; Blanco Murcia, Javier; Mejías López, Elena; Hulverson, Matthew; Choi, Ryan; Arnold, Samuel; Ojo, Kayode; Barrett, Lynn; Hemphill, Andrew; Van Voorhis, Wesley; Ortega Mora, Luis Miguel
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Sánchez Sánchez, Roberto. Universidad Complutense de Madrid; España
Fil: Imhof, Dennis. University of Bern; Suiza
Fil: Hecker, Yanina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible - Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible; Argentina
Fil: Ferre, Ignacio. Universidad Complutense de Madrid; España
Fil: Re, Michela. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Moreno Gonzalo, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Blanco Murcia, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Mejías López, Elena. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Hulverson, Matthew. University of Washington; Estados Unidos
Fil: Choi, Ryan. University of Washington; Estados Unidos
Fil: Arnold, Samuel. University of Washington; Estados Unidos
Fil: Ojo, Kayode. University of Washington; Estados Unidos
Fil: Barrett, Lynn. University of Washington; Estados Unidos
Fil: Hemphill, Andrew. University of Berne. Vetsuisse Faculty. Institute of Parasitology; Suiza
Fil: Van Voorhis, Wesley. University of Berne. Vetsuisse Faculty. Institute of Parasitology; Suiza
Fil: Ortega Mora, Luis Miguel. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Materia
TOXOPLASMA GONDII
ONE HEALTH THERAPEUTICS
BKI-1748
CONGENITAL TOXOPLASMOSIS
SHEEP
SAFETY
EFFICACY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/235546
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/235546
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondiiSánchez Sánchez, RobertoImhof, DennisHecker, Yanina PaolaFerre, IgnacioRe, MichelaMoreno Gonzalo, JavierBlanco Murcia, JavierMejías López, ElenaHulverson, MatthewChoi, RyanArnold, SamuelOjo, KayodeBarrett, LynnHemphill, AndrewVan Voorhis, WesleyOrtega Mora, Luis MiguelTOXOPLASMA GONDIIONE HEALTH THERAPEUTICSBKI-1748CONGENITAL TOXOPLASMOSISSHEEPSAFETYEFFICACYhttps://purl.org/becyt/ford/4.3https://purl.org/becyt/ford/4Congenital 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.Fil: Sánchez Sánchez, Roberto. Universidad Complutense de Madrid; EspañaFil: Imhof, Dennis. University of Bern; SuizaFil: Hecker, Yanina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible - Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible; ArgentinaFil: Ferre, Ignacio. Universidad Complutense de Madrid; EspañaFil: Re, Michela. Universidad Complutense de Madrid. Facultad de Veterinaria; EspañaFil: Moreno Gonzalo, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; EspañaFil: Blanco Murcia, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; EspañaFil: Mejías López, Elena. Universidad Complutense de Madrid. Facultad de Veterinaria; EspañaFil: Hulverson, Matthew. University of Washington; Estados UnidosFil: Choi, Ryan. University of Washington; Estados UnidosFil: Arnold, Samuel. University of Washington; Estados UnidosFil: Ojo, Kayode. University of Washington; Estados UnidosFil: Barrett, Lynn. University of Washington; Estados UnidosFil: Hemphill, Andrew. University of Berne. Vetsuisse Faculty. Institute of Parasitology; SuizaFil: Van Voorhis, Wesley. University of Berne. Vetsuisse Faculty. Institute of Parasitology; SuizaFil: Ortega Mora, Luis Miguel. Universidad Complutense de Madrid. Facultad de Veterinaria; EspañaOxford University Press2023-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/235546Sánchez Sánchez, Roberto; Imhof, Dennis; Hecker, Yanina Paola; Ferre, Ignacio; Re, Michela; et al.; An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii; Oxford University Press; Journal Of Infectious Diseases; 229; 2; 10-2023; 558-5660022-1899CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad470/7331060info:eu-repo/semantics/altIdentifier/doi/10.1093/infdis/jiad470info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:43:07Zoai:ri.conicet.gov.ar:11336/235546instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-12 09:43:07.662CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
title An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
spellingShingle An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
Sánchez Sánchez, Roberto
TOXOPLASMA GONDII
ONE HEALTH THERAPEUTICS
BKI-1748
CONGENITAL TOXOPLASMOSIS
SHEEP
SAFETY
EFFICACY
title_short An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
title_full An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
title_fullStr An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
title_full_unstemmed An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
title_sort An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii
dc.creator.none.fl_str_mv Sánchez Sánchez, Roberto
Imhof, Dennis
Hecker, Yanina Paola
Ferre, Ignacio
Re, Michela
Moreno Gonzalo, Javier
Blanco Murcia, Javier
Mejías López, Elena
Hulverson, Matthew
Choi, Ryan
Arnold, Samuel
Ojo, Kayode
Barrett, Lynn
Hemphill, Andrew
Van Voorhis, Wesley
Ortega Mora, Luis Miguel
author Sánchez Sánchez, Roberto
author_facet Sánchez Sánchez, Roberto
Imhof, Dennis
Hecker, Yanina Paola
Ferre, Ignacio
Re, Michela
Moreno Gonzalo, Javier
Blanco Murcia, Javier
Mejías López, Elena
Hulverson, Matthew
Choi, Ryan
Arnold, Samuel
Ojo, Kayode
Barrett, Lynn
Hemphill, Andrew
Van Voorhis, Wesley
Ortega Mora, Luis Miguel
author_role author
author2 Imhof, Dennis
Hecker, Yanina Paola
Ferre, Ignacio
Re, Michela
Moreno Gonzalo, Javier
Blanco Murcia, Javier
Mejías López, Elena
Hulverson, Matthew
Choi, Ryan
Arnold, Samuel
Ojo, Kayode
Barrett, Lynn
Hemphill, Andrew
Van Voorhis, Wesley
Ortega Mora, Luis Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TOXOPLASMA GONDII
ONE HEALTH THERAPEUTICS
BKI-1748
CONGENITAL TOXOPLASMOSIS
SHEEP
SAFETY
EFFICACY
topic TOXOPLASMA GONDII
ONE HEALTH THERAPEUTICS
BKI-1748
CONGENITAL TOXOPLASMOSIS
SHEEP
SAFETY
EFFICACY
purl_subject.fl_str_mv https://purl.org/becyt/ford/4.3
https://purl.org/becyt/ford/4
dc.description.none.fl_txt_mv 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.
Fil: Sánchez Sánchez, Roberto. Universidad Complutense de Madrid; España
Fil: Imhof, Dennis. University of Bern; Suiza
Fil: Hecker, Yanina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible - Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Instituto de Innovación para la Producción Agropecuaria y el Desarrollo Sostenible; Argentina
Fil: Ferre, Ignacio. Universidad Complutense de Madrid; España
Fil: Re, Michela. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Moreno Gonzalo, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Blanco Murcia, Javier. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Mejías López, Elena. Universidad Complutense de Madrid. Facultad de Veterinaria; España
Fil: Hulverson, Matthew. University of Washington; Estados Unidos
Fil: Choi, Ryan. University of Washington; Estados Unidos
Fil: Arnold, Samuel. University of Washington; Estados Unidos
Fil: Ojo, Kayode. University of Washington; Estados Unidos
Fil: Barrett, Lynn. University of Washington; Estados Unidos
Fil: Hemphill, Andrew. University of Berne. Vetsuisse Faculty. Institute of Parasitology; Suiza
Fil: Van Voorhis, Wesley. University of Berne. Vetsuisse Faculty. Institute of Parasitology; Suiza
Fil: Ortega Mora, Luis Miguel. Universidad Complutense de Madrid. Facultad de Veterinaria; España
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/235546
Sánchez Sánchez, Roberto; Imhof, Dennis; Hecker, Yanina Paola; Ferre, Ignacio; Re, Michela; et al.; An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii; Oxford University Press; Journal Of Infectious Diseases; 229; 2; 10-2023; 558-566
0022-1899
CONICET Digital
CONICET
url http://hdl.handle.net/11336/235546
identifier_str_mv Sánchez Sánchez, Roberto; Imhof, Dennis; Hecker, Yanina Paola; Ferre, Ignacio; Re, Michela; et al.; An early treatment with BKI-1748 exhibits full protection against abortion and congenital infection in sheep experimentally infected with Toxoplasma gondii; Oxford University Press; Journal Of Infectious Diseases; 229; 2; 10-2023; 558-566
0022-1899
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad470/7331060
info:eu-repo/semantics/altIdentifier/doi/10.1093/infdis/jiad470
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.976206

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