Novel approaches to the treatment of sickle cell disease: the potential of histone deacetylase inhibitors

Abstract

Sickle cell disease (SCD) is a severe genetic disorder of hemoglobin causing vaso-occlusion. Patients suffer severe anemia, strokes, renal failure, pulmonary compromise and shortened life expectancy. Over 90,000 people in the USA have SCD, and the options for therapy are limited and only partially effective. With the available therapies – hydroxyurea, blood transfusion, hydration and pain medicines – patients continue to suffer the long-term complications of the disease. This review focuses on the pathogenesis of SCD and the role of fetal hemoglobin in disrupting the polymerization of sickle hemoglobin. The authors review the compounds that induce fetal hemoglobin: hydroxyurea, which is currently US FDA approved, and the histone deacetylase inhibitors and discuss their role in the treatment of SCD and other β-hemoglobinopathies.

Keywords::

• epigenetics
• fetal hemoglobin
• histone deacetylase inhibitors
• hydroxyurea
• panobinostat
• sickle cell disease
• vorinostat

Acknowledgements

The authors wish to thank HF Bunn, RP McCaffrey and N Berliner for critical review of the manuscript. They also thank D Wilpitz for assistance with the figures.

Financial & competing interests of disclosure

This work was funded by a Doris Duke Charitable Foundation Innovations in Clinical Research award and a K12 Harvard Blood Scholars award (5K12HL087164-03). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.