Induction of fetal hemoglobin (HbF) in both sickle cell disease (SCD) and ?-thalassemia is an extremely promising approach to ameliorate the severity of both diseases. Recent molecular studies have revealed new regulators of the fetal-to-adult hemoglobin switch in humans, including BCL11A. BCL11A is a genetically and functionally validated regulator of ?-globin expression and a prime candidate for targeted therapy aimed at induction of HbF in individuals with SCD. Curative treatment for SCD can be attained with hematopoietic stem cell transplantation (HSCT). Graft failure and transplant-related mortality contribute to the significant complications associated with allogeneic HSCT in SCD. Favorable outcomes in SCD are largely dependent on the availability of matched sibling donors and the incidence of graft failure and graft versus host disease (GVHD). Fewer than 10% of SCD patients have unaffected HLA-matched sibling potential donors. Gene therapy for the hemoglobinopathies offers the clear advantage of eliminating the risk of GVHD and the need to identify suitable stem cell donors by the use of autologous cells. Targeting BCL11A in SCD holds the significant advantage that adequate knockdown of BCL11A in erythroid cells derived from gene-modified hematopoietic stem cells (HSCs) will increase HbF expression while concurrently reducing expression of mutant HbS. Since hemoglobin polymerization in sickle red cells is highly dependent on the intracellular concentration of HbS and is strongly inhibited by HbF, vectors effectively targeting BCL11A should prevent the cellular phenotype of sickle-containing red cells. Reduced hemoglobin polymerization would thus lead to a pronounced increase in the red cell half-life in vivo. We have recently shown that that use of erythroid-specific expression of microRNA adapted shRNAs (shRNAmiR) targeting BCL11A effectively induces HbF in human erythroid cells derived from transduced HSCs, largely attenuating the hematologic effects of SCD in a murine model. Based on mathematical modeling and preclinical data, we predict that transduction of human HSCs will reduce red cell sickling in a range that will significantly attenuate the SCD phenotype. Based on these data, we propose a pilot/feasibility study in a limited cohort of SCD patients determine the applicability of this approach.

Public Health Relevance

We have recently discovered a gene that is very important in the control of fetal hemoglobin expression, called BCL11A. Decreasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin, while simultaneously reducing the amount of sickle hemoglobin, in their blood and therefore potentially cure the condition. In this clinical trial, we will use a virus vector to reduce the expression of this gene in red blood cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Qasba, Pankaj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Children's Hospital
United States
Zip Code
Esrick, Erica B; Manis, John P; Daley, Heather et al. (2018) Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Blood Adv 2:2505-2512
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