Wake-up Sleepy Gene: Reactivating Fetal Globin for β-Hemoglobinopathies

Trends Genet. 2018 Dec;34(12):927-940. doi: 10.1016/j.tig.2018.09.004. Epub 2018 Oct 1.

Abstract

Disorders in hemoglobin (hemoglobinopathies) were the first monogenic diseases to be characterized and remain among the most common and best understood genetic conditions. Moreover, the study of the β-globin locus provides a textbook example of developmental gene regulation. The fetal γ-globin genes (HBG1/HBG2) are ordinarily silenced around birth, whereupon their expression is replaced by the adult β-globin genes (HBB primarily and HBD). Over 50 years ago it was recognized that mutations that cause lifelong persistence of fetal γ-globin expression ameliorate the debilitating effects of mutations in β-globin. Since then, research has focused on therapeutically reactivating the fetal γ-globin genes. Here, we summarize recent discoveries, focusing on the influence of genome editing technologies, including CRISPR-Cas9, and emerging gene therapy approaches.

Keywords: CRISPR-Cas9; genome editing; hemoglobinopathies; hereditary persistence of fetal hemoglobin; sickle cell disease; thalassemia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • CRISPR-Cas Systems / genetics
  • Gene Editing / trends
  • Genetic Therapy / trends*
  • Hemoglobinopathies / blood
  • Hemoglobinopathies / genetics*
  • Hemoglobinopathies / pathology
  • Humans
  • Mutation
  • beta-Globins / genetics*
  • beta-Globins / therapeutic use
  • gamma-Globins / genetics*
  • gamma-Globins / therapeutic use

Substances

  • beta-Globins
  • gamma-Globins