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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Comprehensive Center (P60)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Goodman, Jessica; Hassell, Kathryn; Irwin, David et al. (2014) The splenic syndrome in individuals with sickle cell trait. High Alt Med Biol 15:468-71
James, Ellen Butensky; Vreman, Hendrik J; Wong, Ronald J et al. (2010) Elevated exhaled carbon monoxide concentration in hemoglobinopathies and its relation to red blood cell transfusion therapy. Pediatr Hematol Oncol 27:112-21
Jenkins, Zandra A; Hagar, Ward; Bowlus, Christopher L et al. (2007) Iron homeostasis during transfusional iron overload in beta-thalassemia and sickle cell disease: changes in iron regulatory protein, hepcidin, and ferritin expression. Pediatr Hematol Oncol 24:237-43
Styles, Lori A; Abboud, Miguel; Larkin, Sandra et al. (2007) Transfusion prevents acute chest syndrome predicted by elevated secretory phospholipase A2. Br J Haematol 136:343-4
Kuypers, Frans A; Larkin, Sandra K; Emeis, Jef J et al. (2007) Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity. Thromb Haemost 97:478-86
Neumayr, Lynne D; Aguilar, Christine; Earles, Ann N et al. (2006) Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J Bone Joint Surg Am 88:2573-82
Wilson, Leslie S; Moskowitz, Judith Tedlie; Acree, Michael et al. (2005) The economic burden of home care for children with HIV and other chronic illnesses. Am J Public Health 95:1445-52
Vichinsky, Elliott; Butensky, Ellen; Fung, Ellen et al. (2005) Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol 80:70-4
Pakbaz, Zahra; Fischer, Roland; Treadwell, Marsha et al. (2005) A simple model to assess and improve adherence to iron chelation therapy with deferoxamine in patients with thalassemia. Ann N Y Acad Sci 1054:486-91
Fricke, Britta; Jarvis, Helen G; Reid, Cecil D L et al. (2004) Four new cases of stomatin-deficient hereditary stomatocytosis syndrome: association of the stomatin-deficient cryohydrocytosis variant with neurological dysfunction. Br J Haematol 125:796-803

Showing the most recent 10 out of 207 publications