Figure 3.

Concept of dose dependence of BCL11A in relation to a therapeutic level. Of greatest relevance to clinical translation of BCL11A as a target for therapeutic reactivation of HbF is the precise relationship between the level of BCL11A and expression of HbF in vivo. The shape of the curve is unknown. Based on cellular models¹¹ and the level of HbF in haploinsufficient individuals,¹⁵ it is likely that the in vivo level of HbF in the absence of BCL11A would exceed the level needed to correct β-thalassemia and SCD. It will be important in any clinical studies, whether using shRNA knockdown²¹ of BCL11A or gene editing,¹¹ to determine the extent of BCL11A reduction needed to achieve correction.