Therapeutic strategies for sickle cell disease: towards a multi-agent approach.

Published

Journal Article (Review)

For over 100 years, clinicians and scientists have been unravelling the consequences of the A to T substitution in the β-globin gene that produces haemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anaemia, haemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of haemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD - hydroxyurea and L-glutamine - are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD, which arise from a complex network of interdependent pathophysiological processes. In this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal haemoglobin, anti-sickling agents, anti-adhesion agents, modulators of ischaemia-reperfusion and oxidative stress, agents that counteract free haemoglobin and haem, anti-inflammatory agents, anti-thrombotic agents and anti-platelet agents. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies on the basis of SCD pathophysiology is needed to improve the quality of life and survival of people with SCD.

Full Text

Duke Authors

Cited Authors

  • Telen, MJ; Malik, P; Vercellotti, GM

Published Date

  • February 2019

Published In

Volume / Issue

  • 18 / 2

Start / End Page

  • 139 - 158

PubMed ID

  • 30514970

Pubmed Central ID

  • 30514970

Electronic International Standard Serial Number (EISSN)

  • 1474-1784

Digital Object Identifier (DOI)

  • 10.1038/s41573-018-0003-2

Language

  • eng

Conference Location

  • England