The beta hemoglobinopathies do not become manifest until fetal globin (Hb F) is suppressed in infancy, and renewed production of fetal (5') globin decreases complications of these diseases. The need for additional therapeutics which stimulate high proportions of Hb F-containing red blood cells (F-cells) has been recently cited as an unmet priority. Short chain fatty acids (SCFAs) induce beta globin experimentally and in some patients. However, most SCFAs also inhibit erythroid cell growth, which limits the pool of cells in which fetal globin can be induced. Further, the need for IV infusions or large doses, due to rapid metabolism, has made the first SCFA therapies difficult for patient use. We have identified unusual SCFA derivatives, which induce fetal globin in transgenic mice and nonhuman primates, and also stimulate, rather than inhibit, hematopoietic cell proliferation. We hypothesize that mitogenic SCFAs which can be given more often, without dose limitations to prevent cell growth arrest, should induce higher levels of F-cells and beta globin than the growth-inhibitory SCFAs. Five SCFAD candidates with favorable oral PK profiles in baboons have been identified.
The aims of this proposal are: 1) to determine which lead SCFA maximally induces F-cells and beta globin in nonhuman primates long-term, and whether there is additive activity between the novel SCFADs and hydroxyurea; 2) to identify additional T globin-inducing compounds using a computer-modeled pharmacophore, and to determine if any have greater potency, 3) to perform rational selection for preclinical development of candidates for the therapeutic induction of beta globin, and 4) to determine molecular mechanisms of cellular growth stimulation by the mitogenic SCFADs.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Bishop, Terry Rogers
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Faller, Douglas V; Castaneda, Serguei A; Zhou, Daohong et al. (2017) An oral HemokineTM, ?-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo. Blood Cells Mol Dis 63:1-8
Dai, Yan; Sangerman, Jose; Nouraie, Mehdi et al. (2017) Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer. Am J Hematol 92:E10-E11
Dai, Yan; Sangerman, Jose; Luo, Hong Yuan et al. (2016) Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms. Blood Cells Mol Dis 56:62-9
Boosalis, Michael S; Sangerman, Jose I; White, Gary L et al. (2015) Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice. PLoS One 10:e0144660
Perrine, Susan P; Pace, Betty S; Faller, Douglas V (2014) Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am 28:233-48
Inati, Adlette; Kahale, Mario; Perrine, Susan P et al. (2014) A phase 2 study of HQK-1001, an oral fetal haemoglobin inducer, in ?-thalassaemia intermedia. Br J Haematol 164:456-8
Patthamalai, Poramin; Fuchareon, Suthat; Chaneiam, Nattawara et al. (2014) A phase 2 trial of HQK-1001 in HbE-? thalassemia demonstrates HbF induction and reduced anemia. Blood 123:1956-7
Fucharoen, Suthat; Inati, Adlette; Siritanaratku, Noppadol et al. (2013) A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in ?-thalassaemia intermedia and HbE/?-thalassaemia. Br J Haematol 161:587-93
Kutlar, Abdullah; Ataga, Kenneth; Reid, Marvin et al. (2012) A phase 1/2 trial of HQK-1001, an oral fetal globin inducer, in sickle cell disease. Am J Hematol 87:1017-21
Perrine, Susan P; Wargin, William A; Boosalis, Michael S et al. (2011) Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers. J Clin Pharmacol 51:1186-94

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