Carolyn Hoppe, MD, Children’s Hospital Oakland, USA
Although progress continues to be made in the areas of hematopoietic stem cell transplantation and gene therapy with the aim to cure sickle cell disease (SCD), there is still an unmet need for therapeutic interventions aimed at preventing or ameliorating the clinical complications of SCD. With the exception of hydroxyurea and red cell transfusions, few therapeutic options exist for most patients with SCD.
Recent data from genomic and preclinical studies in SCD have provided new opportunities to develop therapeutic strategies targeting key genetic and cellular mechanisms underlying the pathogenesis of SCD. The potential clinical application of several novel treatment strategies will be discussed in this review. Pharmacotherapeutic agents currently under clinical investigation include modulators of Hb F that act by inhibiting DNA methylation (decitabine) or histone deacetylation (dimethylbutyrate, vorinostat and panobinostat) causing changes in chromatin structure and enhanced gamma globin gene expression. Anti-sickling agents that act by increasing oxygen affinity (5-hydroxymethyl-2-furfural/Aes-103), preventing Hb S polymerization (pegylated carboxyhemoglobin/MP4CO) or blocking adenosine signaling (adenosine 2B receptor antagonists) are also being explored. Clinical trials are also underway to evaluate agents targeting pathways of endothelial dysfunction, including selectin inhibitors (GMI-1070, pentosan polysulfate), platelet aggregation (ADP receptor antagonist/prasugrel, GP2a/3b inhibitor/eptifibatide), inflammation (adenosine 2A receptor agonist/ regadenoson, 5-lipooxygenase inhibitor/Zileutron, statins/Zocor,Lipitor), oxidant damage (glutamine).
The identification of molecular and cellular targets for drug development has led to a promising number of clinical studies in SCD. Alternative approaches to clinical trial design, incorporating technological advances, such as non-invasive imaging tools to assess blood flow, are needed to define relevant biological and pharmacokinetic endpoints and facilitate the successful translation of novel therapeutic agents into clinical benefit.