# Gene therapy targeting BCL11A to induce fetal hemoglobin and reduce sickle hemoglobin in patients with Sickle Cell Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $948,587

## Abstract

Induction of fetal hemoglobin (HbF) in both sickle cell disease (SCD) and β-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 γ-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.

## Key facts

- **NIH application ID:** 9928098
- **Project number:** 5R01HL137848-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID A WILLIAMS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $948,587
- **Award type:** 5
- **Project period:** 2017-09-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928098

## Citation

> US National Institutes of Health, RePORTER application 9928098, Gene therapy targeting BCL11A to induce fetal hemoglobin and reduce sickle hemoglobin in patients with Sickle Cell Disease (5R01HL137848-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928098. Licensed CC0.

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