Correction of the sickle cell mutation in embryonic stem cells.

Sickle cell anemia is one of the most common genetic diseases worldwide. Patients often suffer from anemia, painful crises, infections, strokes, and cardiopulmonary complications. Although current management has improved the quality of life and survival of patients, cure can be achieved only with bone marrow transplantation when histocompatible donors are available. The ES cell technology suggests that a therapeutic cloning approach may be feasible for treatment of this disease. Using a transgenic/knockout sickle cell anemia mouse model, which harbors 240 kb of human DNA sequences containing the beta(S)-globin gene, we prepared ES cells from blastocysts that had the sickle cells anemia genotype and carried out homologous recombination with DNA constructs that contained the beta(A)-globin gene. We obtained ES cells in which the beta(S) was corrected to the beta(A) sequence. Hematopoietic cells differentiated from these ES cells produced both hemoglobin A and hemoglobin S. This approach can be applied to human ES cells to correct the sickle mutation as well as beta-thalassemia mutations.