Review Article | Published:

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

Nature Reviews Drug Discoveryvolume 18pages139158 (2019) | Download Citation

Abstract

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.

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Acknowledgements

This work was partially supported by the following grant awards from the US National Institutes of Health: R21DK106509 (National Institute of Diabetes and Digestive and Kidney Diseases; to M.J.T.), U01-HL117709 and RO1-HL112603 (National Heart, Lung and Blood Institute (NHLBI); to P.M.) and R01HL114567 (NHLBI; to G.M.V.). M.J.T. and P.M. also received support from the Doris Duke Charitable Foundation.

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  1. Division of Hematology, Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University, Durham, NC, USA

    • Marilyn J. Telen
  2. Division of Experimental Hematology and Cancer Biology and the Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Punam Malik
  3. Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    • Gregory M. Vercellotti

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All authors contributed equally to the conception, writing and editing of this manuscript.

Competing interests

M.J.T., P.M. and G.M.V. have been involved in clinical and/or basic research involving multiple compounds and therapeutic strategies discussed in this article.

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Correspondence to Marilyn J. Telen.

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https://doi.org/10.1038/s41573-018-0003-2