Investigational agents for sickle cell disease.

Developments in the treatment of sickle cell disease (SCD) have not kept pace with advances in understanding the pathophysiology of this haemoglobinopathy. Drugs undergoing preclinical and clinical assessment for the therapy of these globin gene disorders are discussed in this article. Beginning with investigational agents for treatment of SCD as a whole, the discussion proceeds to drugs being developed for specific manifestations or iatrogenic complications. Despite being licensed in the USA, the prototype antisickling agent, hydroxycarbamide, has not attained worldwide clinical use because of concerns about long-term toxicity. The less toxic decitabine, which (as with hydroxycarbamide) increases fetal haemoglobin level, cannot be administered orally; therefore, the search continues for effective and safe antisickling drugs that can be taken orally. The naturally occurring benzaldehyde 5-hydroxymethyl-2-furfural has shown promising antisickling properties in vitro, and when administered to transgenic sickle mice. These effects are surpassed by the new synthetic pyridyl derivatives of benzaldehyde. Studies in humans with SCD are required to assess the clinical efficacy of these benzaldehydes. Niprisan, another antisickling agent with significant clinical efficacy and an attractive safety profile, is undergoing further development. The prospects of antiadhesion therapy in SCD are demonstrated by a recombinant protein containing the Fc fragment of IgG fused to the natural ligand for selectins: the conjugate significantly inhibited blood vessel occlusion in transgenic sickle mice. Whereas the orally administrable iron-chelating agent deferasirox is likely to increasingly take the place of desferioxamine (which can only be given parenterally), effective treatment of priapism in SCD remains a distressing challenge.