The Efficacy of Butyric Acid in Ameliorating Clinical Symptoms of Sickle Cell Disease

Abstract

Statistics from the CDC and NIH indicate that 70,000 to 80,000 people in the United States have SCD. The disease is estimated to occur in 1 in 500 African Americans and 1 in 1,000 to 1,400 Hispanic Americans. Over half of the individuals with homozygous HbS disease, experience very painful intermittent vaso-occlusive crises aka sickle-cell crises. Vaso-occlusion results in not only recurrent painful episodes but a variety of serious organ system complications that cause significant morbidity and mortality. Allogeneic bone marrow transplantation (BMT) can cure SCD, but many risks are associated with BMT and lack of availability of a matched donor limit the utility of BMT. Stem cell transplantation can also be used to treat SCD, but much like BMT, it has many limitations and safety issues. Pharmacologic agents that elevate hemoglobin F (HbF) have been used in the treatment of SCD, mainly in adults but also, in high-risked children. Hydroxyurea, an antineoplastic drug, is the only HbF inducing drug currently approved by the FDA for such use. It works in only about two-thirds of people with SCD and even in those cases it sometimes stops working over time. Of greater concern, however, is that hydroxyurea is a potential leukemogenic, carcinogenic, teratogenic agent. Other serious side effects from long-term use include hepatotoxicity and infertility. Chemotherapeutic drugs such as decitabine and 5-azacytidine are being used off-label and they have serious adverse effects as well. Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly non-cytotoxic therapeutics. HbF is established as a major regulator of SCD severity; increased HbF levels correlate with milder clinical courses and improved survival. The discovery in 1975, of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-butyric acid (DBA), as a non-toxic anti-sickling agent has stimulated ongoing research into its therapeutic benefits in the treatment of SCD. The research shows that it is the ability of butyric acid to increase fetal hemoglobin without toxic effects that makes it noteworthy in the treatment of SCD. The review of the clinical data associated with butyric acid and its derivatives and their efficacy in ameliorating the clinical symptoms of SCD is the objective of this thesis. Please note that for this investigation, the terms butyric acid and butyrate will be used interchangeably. Also, butyrate derivatives will be considered as butyrate would in regards to efficacy in ameliorating clinical symptoms of SCD.