Benserazide racemate and enantiomers induce fetal globin gene expression in vivo: Studies to guide clinical development for beta thalassemia and sickle cell disease

Betty S. Pace, Susan Perrine, Biaoru Li, Levi Makala, Hongyan Xu, Mayuko Takezaki, Roman F. Wolf, Amy Wang, Xin Xu, Junfeng Huang, Asaf Alimardanov, Gregory J. Tawa, Jose Sangerman, Aidan Faller, Wei Zheng, London Toney, Sharie J. Haugabook

Research output: Contribution to journalArticlepeer-review

Abstract

Increased expression of developmentally silenced fetal globin (HBG) reduces the clinical severity of β-hemoglobinopathies. Benserazide has a relatively benign safety profile having been approved for 50 years in Europe and Canada for Parkinson's disease treatment. Benserazide was shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed fetal hemoglobin (HbF) induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice containing the entire human β-globin gene (β-YAC) and anemic baboons. The goal of this study is to evaluate efficacies and plasma exposure profiles of benserazide racemate and its enantiomers to select the chemical form for clinical development. Intermittent treatment with all forms of benserazide in β-YAC mice significantly increased proportions of red blood cells expressing HbF and HbF protein per cell with similar pharmacokinetic profiles and with no cytopenia. These data contribute to the regulatory justification for development of the benserazide racemate. Additionally, dose ranges and frequencies required for HbF induction using racemic benserazide were explored. Orally administered escalating doses of benserazide in an anemic baboon induced γ-globin mRNA up to 13-fold and establish an intermittent dose regimen for clinical studies as a therapeutic candidate for potential treatment of β-hemoglobinopathies.

Original languageEnglish (US)
Article number102561
JournalBlood Cells, Molecules, and Diseases
Volume89
DOIs
StatePublished - Jul 2021

Keywords

  • Anemic baboon
  • Benserazide
  • Beta YAC transgenic mouse
  • Beta hemoglobinopathies
  • Fetal hemoglobin

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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