Sickel Cell Disease: From Mice to Men
and Everything in Between

By Zoe L. Larned, M.D., and
Thomas L. Ortel, M.D., Ph.D.

The first report of a patient with anemia, recurrent pain, and sickled red blood cells appeared in 1910. Almost 80 years later, the first reports of a transgenic mouse expressing the ß gene appeared. The Education Session Hemoglobinopathies spanned clinical observations and mouse model studies and highlighted novel therapeutic treatments being evaluated in the management of sickle cell disease (SCD), new understanding of the pathophysiology of SCD gained from advances in experimental mouse models, and guidelines for the management of stroke.

Some of the most exciting advances in sickle cell anemia have occurred with the identification and clinical evaluation of new drugs that increase the level of fetal hemoglobin (HbF). Drs. Joseph DeSimone and Yogen Saunthararajah reviewed the mechanism of action and highlighted some of the recent studies with decitabine, an analogue of 5-azacytidine. Low dose decitabine is shown to effectively stimulate HbF production with minimal toxicity in patients including those who have failed to respond to treatment with hydroxyurea (HU) therapy in the past.

Drs. George F. Atweh, Hassana Fathallah, and Rona S. Weinberg highlighted some of the recent clinical investigations with butyrate as single agent therapy and in combination with HU and nicely reviewed some of the laboratory studies that have sought to elucidate its mechanism of action. While the mechanism of action of butyrate in activating y–globin gene expression is not fully understood, the review makes it clear that it is different than that of HU and that it is likely that these drugs in combination induce HbF production in an additive or synergistic way. The development and understanding of drugs that target a variety of pathways in the pathogenesis of SCD and the possibilities that combination therapy may offer provide an exciting future in the approach to SCD.

Developments in transgenic sickle mice experimental models were highlighted by Drs. Ronald L. Nagel and Mary E. Fabry. They reviewed the contributions made to the understanding of both the pathophysiology of SCD and the testing of therapeutics, including gene therapy, gained from these models.

Guidelines for the prevention and management of stroke were offered by Dr. Robert J. Adams. Since little is known regarding the mechanism of stroke in adult patients with SCD, as opposed to children, and since there is limited data regarding treatment and prevention of stroke in this population, the recommendations are largely drawn from those for adults without SCD. However, Dr. Adams nicely highlighted that as adults with SCD are living longer and facing other age-related comorbidities (hypertension, hyperlipidemia, diabetes) that the prevention and treatment of stroke becomes increasingly important.

Much remains to be learned about sickle cell disease, but the work presented at these presentations documents how far we have come.