Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing

Jian Xu, Cong Peng, Vijay G. Sankaran, Zhen Shao, Erica B. Esrick, Bryan G. Chong, Gregory C. Ippolito, Yuko Fujiwara, Benjamin L. Ebert, Philip W. Tucker, Stuart H. Orkin

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Persistence of human fetal hemoglobin (HbF, α2γ 2) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

Original languageEnglish (US)
Pages (from-to)993-996
Number of pages4
JournalScience
Volume334
Issue number6058
DOIs
StatePublished - Nov 18 2011

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Fetal Hemoglobin
Sickle Cell Anemia
Thalassemia
Globins
Transgenic Mice
Proteins
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., ... Orkin, S. H. (2011). Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science, 334(6058), 993-996. https://doi.org/10.1126/science.1211053

Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. / Xu, Jian; Peng, Cong; Sankaran, Vijay G.; Shao, Zhen; Esrick, Erica B.; Chong, Bryan G.; Ippolito, Gregory C.; Fujiwara, Yuko; Ebert, Benjamin L.; Tucker, Philip W.; Orkin, Stuart H.

In: Science, Vol. 334, No. 6058, 18.11.2011, p. 993-996.

Research output: Contribution to journalArticle

Xu, J, Peng, C, Sankaran, VG, Shao, Z, Esrick, EB, Chong, BG, Ippolito, GC, Fujiwara, Y, Ebert, BL, Tucker, PW & Orkin, SH 2011, 'Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing', Science, vol. 334, no. 6058, pp. 993-996. https://doi.org/10.1126/science.1211053
Xu, Jian ; Peng, Cong ; Sankaran, Vijay G. ; Shao, Zhen ; Esrick, Erica B. ; Chong, Bryan G. ; Ippolito, Gregory C. ; Fujiwara, Yuko ; Ebert, Benjamin L. ; Tucker, Philip W. ; Orkin, Stuart H. / Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. In: Science. 2011 ; Vol. 334, No. 6058. pp. 993-996.
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abstract = "Persistence of human fetal hemoglobin (HbF, α2γ 2) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.",
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