Faculty Member Michel Sadelain

Memorial Sloan-Kettering Cancer Center researchers have demonstrated in mice that red blood cell precursors derived from bone marrow stem cells could be engineered to produce a secreted protein at therapeutic levels over a prolonged period. This strategy -- involving transfer of a therapeutically useful gene into DNA of stem cell-derived red blood cell precursors -- may theoretically be safer than current stem cell-based gene therapies, in which inserted genes are activated in all stem cell-derived cells, increasing the risk of undesirable mutations.

Because maturing red blood cells produce protein so efficiently, Memorial Sloan-Kettering geneticist Michel Sadelain and colleagues tested the ability of red blood cell precursors to express a clotting factor in hemophiliac mice lacking clotting factor IX. The introduced gene received a boost from the beta-globin promoter -- a DNA sequence that specifically kick-starts gene expression in red blood cell precursors. Not only did the beta-globin promoter initiate gene expression and facilitate protein secretion, as evidenced by restored blood-clotting function in mice, but the precursor cells generated 20 times more protein than obtained with a standard promoter commonly used to genetically engineer blood-forming stem cells and other cells.

"The beta-globin system could eventually be used to generate long-term secretion of proteins that treat genetic disorders, infectious diseases, and cancer," said Dr. Sadelain. Results were published in August in Nature Biotechnology. [PubMed Abstract]