The sickle cell genes are adult globin genes that are developmentally turned on and replace fetal globin expression, producing disease at 4-6 months of age. Continued expression of small amounts of fetal globin has been shown by many parameters, including inhibiting polymerization of sickle hemoglobin in vitro and ameliorating clinical symptoms in large populations of afflicted patients, to provide a method of preventing clinical disease in the beta globin disorders. While chemotherapeutic agents are being tested for this purpose in adult patients, there are appropriate reservations about giving cytotoxic and mutagenic agents to children for long periods of time.
The aim of this proposal is to develop another class of compounds, butyric acid and its analogues, for children with beta globin disorders. We propose clinical trials of butyrate compounds based on previous findings that 1) elevated levels of alpha amino-n-butyric acid in infants to diabetic mothers prevents the normal suppression of fetal globin before birth, 2) butyrate analogues increase fetal globin expression in erythroid progenitors cultured from patients of all ages, 3) butyrate specifically increases expression from the gamma globin gene promoter, and 4) these compounds increase embryonic and fetal globin synthesis in animal models. Butyric acid and a long-acting analogue, Isobutyramide, will therefore be administered in Phase I studies to establish doses that can reproducibly stimulate fetal globin production in the developing erythroblast in vivo. Phase II trials will be performed with the more effective and/or practical compound, in which dosing schedules for efficacy and compliance will be established. The goal of treatment is to develop a butyrate-based treatment regimen that can maintain at least 4-8% gamma globin synthesis, 70% F-cells, and 25% Hb F or more in the peripheral circulation. Our preliminary data in animals and in patients strongly suggests these goals can be achieved.
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