Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing

Abstract

Persistence of human fetal hemoglobin (HbF, α2γ2) 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.

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

“…KO of BCL11A in mice carrying a human β-globin cluster transgene leads to profound delay in globin switching and impaired HbF silencing in adult erythroid cells (5,8). Previously silenced γ-globin genes can also be reactivated by loss of BCL11A in adult animals (8). Most importantly, inactivation of BCL11A alone is sufficient to ameliorate the hematologic and pathologic defects associated with SCD through high-level HbF induction in humanized mouse models (8).…”

“…BCL11A protein is developmentally regulated and is required to maintain HbF silencing in human adult erythroid cells (4,5). KO of BCL11A in mice carrying a human β-globin cluster transgene leads to profound delay in globin switching and impaired HbF silencing in adult erythroid cells (5,8). Previously silenced γ-globin genes can also be reactivated by loss of BCL11A in adult animals (8).…”

BCL11Acontrôle l’expression de l’hémoglobine fœtale

“…Un travail plus récent des mêmes auteurs, précisant le rôle majeur de BCL11A dans un modèle murin de dré-panocytose, a l'intérêt d'ouvrir des perspectives thérapeutiques [12]. Les auteurs ont introduit dans des souris transgéniques l'ensemble du locus -globine humain, porteur de la mutation  S , dans un YAC (yeast artificial chromosome) et vérifié que le phénotype de ces souris reproduisait la maladie drépanocytaire.…”

Pluripotent Stem Cells in Research and Treatment of Hemoglobinopathies

“…There are two humanized mouse models of SCA, the "Berkeley" mouse and the "Townes" mouse, which have proven valuable in studying disease mechanisms and testing therapeutic strategies, such as gene therapy (Pawliuk et al 2001;Xu et al 2011). The Berkeley mouse is a transgenic strain engineered to express normal human a-globin and g-globin as well as b S -globin, the sickle cell mutant (Paszty et al 1997).…”