Stem cells researchers from the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles (UCLA) have shown that a new stem cell gene therapy protocol can potentially lead to a one-time, lasting treatment for sickle-cell disease, which remains the nation’s most common inherited blood disorder.
This study was led by Dr. Donald Kohn and was published March 2 in the journal Blood. This paper details a method that repairs a mistake in the beta-globin that causes sickle-cell disease and, for the first time, shows that such a gene therapy technique can lead to the production of normal red blood cells.
People with sickle-cell disease are born with a mutation in their beta-globin gene.
Beta-globin is one of the protein chains that compose the protein hemoglobin. Hemoglobin is the protein in red blood cells that ferries oxygen from the lungs to the tissues and then returns to the lungs to load up with oxygen again and then goes back to the tissues. Red blood cells, which are made in the bone marrow, are packed from stem to stern with hemoglobin molecules, and normally are round, and slightly dished and flexible enough to squeeze through small capillary beds in tissues. The mutation in the beta-globin gene that causes sickle-cell disease, however, causes hemoglobin to form long, stiff rods of protein rather than tight, compactly packed clusters of hemoglobin. These protein rods deform the red blood cells and make them stiff, sickle-shaped, and unable to pass through tissue capillary beds.
These abnormally shaped red blood cells not only move poorly through blood vessels, but they also do not sufficiently carry oxygen to vital organs.
The stem cell gene therapy method described by Kohn and his colleagues corrects the mutation in the beta-globin gene in the bone marrow-based stem cells so that they produce normal, circular-shaped blood cells. The technique uses specially engineered enzymes, called zinc-finger nucleases, to eliminate the mutation and replace it with a corrected version that repairs the beta-globin mutation. Kohn’s research showed that this method has the potential to treat sickle-cell the disease if the gene therapy achieves higher levels of correction.
“This is a very exciting result,” said Dr. Kohn, professor of pediatrics and microbiology, immunology and molecular genetics. “It suggests the future direction for treating genetic diseases will be by correcting the specific mutation in a patient’s genetic code. Since sickle-cell disease was the first human genetic disease where we understood the fundamental gene defect, and since everyone with sickle-cell has the exact same mutation in the beta-globin gene, it is a great target for this gene correction method.”