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Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia

Effective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that th...

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Autores principales: Safeukui, Innocent, Ware, Russell E., Mohandas, Narla, Haldar, Kasturi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580175/
https://www.ncbi.nlm.nih.gov/pubmed/37093647
http://dx.doi.org/10.1182/bloodadvances.2022009124
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author Safeukui, Innocent
Ware, Russell E.
Mohandas, Narla
Haldar, Kasturi
author_facet Safeukui, Innocent
Ware, Russell E.
Mohandas, Narla
Haldar, Kasturi
author_sort Safeukui, Innocent
collection PubMed
description Effective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that the HU treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We used physiologically relevant drug exposures that mimic in vivo pharmacokinetics in humans. Under these conditions, we showed that HU and other ribonucleotide reductase (RNR) inhibitors have significant, intrinsic killing activity in vitro against schizont stages of P falciparum in both normal and sickle red blood cells. Long-term in vitro selection with HU increased the expression of Pfrnr genes but showed a low risk of eliciting stably resistant parasites or compromising the potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, and long-term use of HU for SCA in malaria-endemic countries and provide a novel biological model for the treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting.
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spelling pubmed-105801752023-10-18 Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia Safeukui, Innocent Ware, Russell E. Mohandas, Narla Haldar, Kasturi Blood Adv Red Cells, Iron, and Erythropoiesis Effective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that the HU treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We used physiologically relevant drug exposures that mimic in vivo pharmacokinetics in humans. Under these conditions, we showed that HU and other ribonucleotide reductase (RNR) inhibitors have significant, intrinsic killing activity in vitro against schizont stages of P falciparum in both normal and sickle red blood cells. Long-term in vitro selection with HU increased the expression of Pfrnr genes but showed a low risk of eliciting stably resistant parasites or compromising the potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, and long-term use of HU for SCA in malaria-endemic countries and provide a novel biological model for the treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting. The American Society of Hematology 2023-04-26 /pmc/articles/PMC10580175/ /pubmed/37093647 http://dx.doi.org/10.1182/bloodadvances.2022009124 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Red Cells, Iron, and Erythropoiesis
Safeukui, Innocent
Ware, Russell E.
Mohandas, Narla
Haldar, Kasturi
Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title_full Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title_fullStr Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title_full_unstemmed Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title_short Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
title_sort simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia
topic Red Cells, Iron, and Erythropoiesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580175/
https://www.ncbi.nlm.nih.gov/pubmed/37093647
http://dx.doi.org/10.1182/bloodadvances.2022009124
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