Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

Betty Sue Pace, Li Liu, Biaoru Li, Levi H Makala

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and β-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in β-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the γ-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence γ-globin during development have been targeted for gene therapy in β-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance γ-globin expression and have the potential for future drug development to treat the β-hemoglobinopathies.

Original languageEnglish (US)
Pages (from-to)1050-1064
Number of pages15
JournalExperimental Biology and Medicine
Volume240
Issue number8
DOIs
StatePublished - Jan 1 2015

Fingerprint

Cell signaling
Fetal Hemoglobin
Sickle Cell Anemia
Globins
Sickle Hemoglobin
Hemoglobinopathies
Pharmaceutical Preparations
Thalassemia
Developmental Gene Expression Regulation
Repressor Proteins
Hemoglobin A
Gene therapy
Gene expression
Polymerization
Genetic Therapy
Transcription Factors
Genes
Parturition
Pharmacology
Mutation

Keywords

  • Fetal hemoglobin
  • NRF2
  • cell signaling
  • p38 MAPK
  • sickle cell disease
  • β-hemoglobinopathies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction : Strategies to treat sickle cell disease. / Pace, Betty Sue; Liu, Li; Li, Biaoru; Makala, Levi H.

In: Experimental Biology and Medicine, Vol. 240, No. 8, 01.01.2015, p. 1050-1064.

Research output: Contribution to journalArticle

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