The beta-thalassemias are serious blood diseases, caused by diverse molecular mutations affecting the beta-chain of adult hemoglobin A, (a2b2), and are designated as a global health burden. The conditions have early mortality and no approved definitive therapy. Fetal globin (HbF, a2g2) is the major modulator of disease severity, and increasing its synthesis is established to reduce globin imbalance and ameliorate these conditions. A challenge to successful application of HbF inducers in the beta-thalassemias has been the genetic heterogeneity, which produces variable baseline fetal globin levels (and as yet unpredictable) responsiveness to HbF-inducing therapeutics between individuals. This proposal combines two distinct investigative approaches: 1) a long-term investigation to identify high potency, molecularly-based therapeutics to induce HbF, and 2) expertise in identifying thalassemia genotypes, modifiers, and mechanisms which modulate severity. First, two drug discovery screening campaigns, using molecular modeling or high throughput screening (HTS), have identified a select panel of novel, structurally-unrelated, high-potency HbF-inducing therapeutics, including some drugs already FDA-approved for other indications. Second, a 5-year genome wide screening (GWAS) study in international patient populations identified 3 influential polymorphisms, or quantitative trait loci, (QTL), associated with elevated HbF, less clinical severity, and mechanism of action. We will apply these 2 experiences to determine 1) which novel therapeutics most effectively augment HbF in erythroid cells cultured from beta thalassemia patients, genotyped for 2 major subtypes of thalassemia, or patients with sickle cell disease, and the 3 influential genetic modifier (QTL) profiles;2) molecular mechanisms of action of the new therapeutic agents, and 3) combinations of the targeted therapeutics, which are most potent in erythroid cells cultured from different subsets +/- epigenetic inducing agents. This work will provide a basis for evaluating the optimal therapeutics in patients most likely to respond favorably in clinical trials.
Our Aims i nclude:
Aim I : To determine which novel therapeutics enhance gamma globin expression most effectively in erythroid cells cultured from patients genotyped for beta thalassemia mutations and the 3 influential QTLs.
Aim II : To determine molecular effects of the novel therapeutics on select known components of repressors of the fetal globin gene promoter and if the three HbF QTLs correlate with more or less robust responses to select inducing agents. Determine if new therapeutics suppress components of established repressor complexes (BCL-11A, Sox 6, HDAC-3). Determine whether differences in QTL profiles correlate with responses or lack thereof to different gamma globin inducing therapeutics.
Aim III : To determine if a combination of an epigenetic-acting HbF inducer and a promoter-targeted inducer will produce more potent HbF induction than single agents alone, in the beta thalassemia subsets and in HbSS erythroid cells with low baseline HbF.

Public Health Relevance

The beta thalassemias and hemoglobinopathies are serious blood diseases caused by molecular mutations affecting the beta globin chain of adult hemoglobin, which carries oxygen in red blood cells, and are designated a global health burden. Fetal globin, another type, which is suppressed in infancy, can replace the missing globin or prevent the effects of mutant beta globin, and is established as a target for drug therapy, but has been difficult to implement in these genetically diverse conditions. This proposal will investigate a panel of FDA-approved therapeutics to reactivate fetal globin in blood cells cultured from patients who are characterized for genetic modifiers, and will determine which therapeutics are most effective in different patient subsets, thus providing a sound basis for rapid clinical application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052962-11
Application #
8594239
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
1998-06-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$320,443
Indirect Cost
$124,693
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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
Boosalis, Michael S; Castaneda, Serguei A; Trudel, Marie et al. (2011) Novel therapeutic candidates, identified by molecular modeling, induce ýý-globin gene expression in vivo. Blood Cells Mol Dis 47:107-16
Terse, Pramod S; Johnson, Jerry D; Hawk, Michael A et al. (2011) Short-term toxicity study of ST-20 (NSC-741804) by oral gavage in Sprague-Dawley rats. Toxicol Pathol 39:614-22
Perrine, Susan P; Castaneda, Serguei A; Chui, David H K et al. (2010) Fetal globin gene inducers: novel agents and new potential. Ann N Y Acad Sci 1202:158-64
Perrine, Susan P; Mankidy, Rishikesh; Boosalis, Michael S et al. (2009) Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol 82:466-76
Perrine, Susan P (2008) Fetal globin stimulant therapies in the beta-hemoglobinopathies: principles and current potential. Pediatr Ann 37:339-46
Nguyen, Toan D; Kim, Ug-Sung; Perrine, Susan P (2006) Novel short chain fatty acids restore chloride secretion in cystic fibrosis. Biochem Biophys Res Commun 342:245-52

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