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

Nature Reviews Drug Discovery volume 18, pages 139–158 (2019)Cite this article

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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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Fig. 1: Pathophysiology of sickle cell disease.
Fig. 2: Sickle cell disease pathophysiological pathways and opportunities for targeted therapy.
Fig. 3: The pipeline of sickle cell disease therapies.

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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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  1. Marilyn J. Telen
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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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Telen, M.J., Malik, P. & Vercellotti, G.M. Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat Rev Drug Discov 18, 139–158 (2019). https://doi.org/10.1038/s41573-018-0003-2

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