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

Abstract

Effective treatments for genetic disorders that co-evolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anaemia (SCA) by reducing clinical complications, transfusions, and death. Despite concerns that 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 utilized 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 expression of Pfrnr genes but showed low risk of eliciting stably resistant parasites or compromising 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, long-term use of HU for SCA in malaria endemic countries and provide a novel biological model for treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting.

F‐erythrocytes promote Plasmodium falciparum proliferation in sickle cell disease

“…In addition, Safeukui et al recently demonstrated hydroxyurea and other ribonucleotide reductase inhibitors reduce schizont development by nearly 40% in HbSS erythrocytes. 40 A question remains, however, whether HbF could increase the risk of malaria in select individuals, particularly infants and those with known congenital or GT-modified HbF inducers.…”

“…In a secondary analysis of the subjects in the REACH study, the authors found that participants had a lower incidence of malaria after starting hydroxyurea therapy compared with prior treatment. In addition, Safeukui et al recently demonstrated hydroxyurea and other ribonucleotide reductase inhibitors reduce schizont development by nearly 40% in HbSS erythrocytes 40 . A question remains, however, whether HbF could increase the risk of malaria in select individuals, particularly infants and those with known congenital or GT‐modified HbF inducers.…”

Hydroxyurea reduces infections in children with sickle cell anemia in Uganda

“… 20 In murine models, hydroxyurea decreased parasitemia, prevented experimental cerebral malaria, 21 and had direct activity against schizont stages of malaria. 22 Together, these data suggest that hydroxyurea may have both immunomodulatory and antimicrobial effects that reduce the risk of infections.…”

Further evidence supporting the global use of hydroxyurea

“…In this issue of Blood Advances , Safeukui et al demonstrate the antimalarial properties of hydroxyurea, a ribonucleotide reductase (RNR) inhibitor, found to be a safe and efficacious therapy used to manage sickle cell disease (SCD) in children and adults. 1 The World Health Organization estimates that a child dies of malaria every 2 minutes. 2 In addition, SCD, a deadly inherited hemoglobinopathy, characterized by severe anemia and painful vaso-occlusive crises resulting in pain and/or end-organ dysfunction, affects over 300 000 newborns annually, 3 predominantly in regions endemic for malaria.…”