Sickle cell disease (SCD) is the most common hemoglobinopathy and one of the most common monogenic diseases in the world. SCD poses a major public health burden in the US with an aggregate charge for health care services of $1 billion. Globally, mortality, particularly in young children is very high. The goal of the proposed collaborative project is to develop new methods to treat SCD disease, with the realization that near term, high tech approaches involving genetic therapies applicable in the US will need to be replaced with inexpensive low-tech approaches utilizing targeted oral drugs that can be also be utilized in the developing areas of the world. Th focus of this application is thus to leverage state-of-the-art chemical and biological approaches to increase the expression of fetal hemoglobin to ameliorate the morbidity and cost of treatment of SCD. The proposed program seeks to take advantage of recent scientific breakthroughs, rapidly advancing technology and the environment of several outstanding research institutions to drive the translational agenda in this disease. The overarching theme of this multidisciplinary grant application is to utilize innovative scientific approaches to identify and put into clinical investigation new therapeutic modalities that modulate gamma-globin expression. There are three projects: i) integrating more traditional molecular hematology approaches, translational research, and approaches from the field of metabolism to identify new inducers of y-globin; ii) modulation of Bell 1A expression to increase HbF; iii) identifying HDAC inhibitors with optimal selectivity to maximize induction of y-globin expression while minimizing toxicity. Utilizing the established foundation of a highly sophisticated translational research program that focuses on clinical gene and cell therapy and anchors the Translational Research Skills Development Core, advice from world-renown senior investigators in SCD and globin biology at Children's Hospital Boston (CHB) and harnessing new scientific expertise not previously focusing on hemoglobinopathies at CHB, Brigham and Women's Hospital and the Broad Institute rapid migration of the scientific discoveries emanating from this program into pre-clinical and then clinical testing is likely.

Public Health Relevance

Sickle cell disease (SCD) is the most common hemoglobinopathy and one of the most common monogenic diseases in the world. SCD poses a major public health burden in the US with an aggregate charge for health care services of $1 billion. The goal of the proposed project is to develop new methods to treat SCD disease involving genetic therapies and approaches utilizing mechanism-based targeted oral drugs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1)
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Qasba, Pankaj
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Children's Hospital Boston
United States
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Park, Hee Ho; Triboulet, Robinson; Bentler, Martin et al. (2018) DROSHA Knockout Leads to Enhancement of Viral Titers for Vectors Encoding miRNA-Adapted shRNAs. Mol Ther Nucleic Acids 12:591-599
Kim, Ah Ram; Sankaran, Vijay G (2018) Thrombopoietin: tickling the HSC's fancy. EMBO Mol Med 10:10-12
Thrasher, Adrian J; Williams, David A (2017) Evolving Gene Therapy in Primary Immunodeficiency. Mol Ther 25:1132-1141
Fiorini, Claudia; Abdulhay, Nour J; McFarland, Sean K et al. (2017) Developmentally-faithful and effective human erythropoiesis in immunodeficient and Kit mutant mice. Am J Hematol 92:E513-E519
Ludwig, Leif S; Khajuria, Rajiv K; Sankaran, Vijay G (2016) Emerging cellular and gene therapies for congenital anemias. Am J Med Genet C Semin Med Genet 172:332-348
Abdulhay, Nour; Fiorini, Claudia; Kumánovics, Attila et al. (2016) Normal hematologic parameters and fetal hemoglobin silencing with heterozygous IKZF1 mutations. Blood 128:2100-2103
Nandakumar, Satish K; Ulirsch, Jacob C; Sankaran, Vijay G (2016) Advances in understanding erythropoiesis: evolving perspectives. Br J Haematol 173:206-18
Basak, Anindita; Sankaran, Vijay G (2016) Regulation of the fetal hemoglobin silencing factor BCL11A. Ann N Y Acad Sci 1368:25-30
Brendel, Christian; Guda, Swaroopa; Renella, Raffaele et al. (2016) Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J Clin Invest 126:3868-3878
Wakabayashi, Aoi; Sankaran, Vijay G (2016) Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis-what patients can teach us about blood cell production. Pediatr Res 79:366-70

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