Butyrate derivatives. New agents for stimulating fetal globin production in the beta-globin disorders.

PURPOSE

Stimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and beta-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors.

PATIENTS AND METHODS

Due to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4-8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of approximately 20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects.

RESULTS

Butyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun.

CONCLUSIONS

These agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and beta-thalassemia.