Abstract

The overall goal of this research proposal is to test the hypothesis that stable gamma-globin inducers which do not inhibit erythroid cell proliferation and may be given frequently, will result in superior long-term hemoglobin F inducibility in the absence of hematologic suppression in vivo.
Specific aims are to: 1) identify oral fetal globin gene inducers with favorable in vivo kinetics; 2) determine the effects of long term administration of oral hemoglobin F inducers in non-human primates; and 3) determine whether synergy results with their combined use with other compounds known to stimulate HbF production. The primary screen for gamma-globin inducibility will be performed using K562 cells alone and those stably transfected with promoter/reporter constructs, erythroid progenitor cultures and a responsive multi-lineage cell line. Hemoglobin F inducers which stimulate or do not inhibit erythropoiesis in vitro will be studied in baboons to determine oral pharmacokinetics, safety and to develop effective long-term regimens.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052962-04
Application #
6381412
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1998-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2003-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$346,758
Indirect Cost

  Institution

Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118

  Publications

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

Showing the most recent 10 out of 24 publications