In a recently published study in the magazine Science, authors report they have corrected sickle cell anemia in mice using reprogrammed stem cells, a technique introduced by Japanese scientists. While many study teams have been advancing research on reprogrammed stem cells, this most recent breakthrough is the first to actually correct a disease in mice through this method.
The researchers responsible for the breakthrough are from The Whitehead Institute for Biomedical Research in Cambridge, MA, the Department of Biochemistry and Molecular Genetics at the University of Alabama at Birmingham and the Department of Biology at the Massachusetts Institute of Technology, also in Cambridge.
Sickle cell anemia is an inherited disorder caused by a single gene mutation. The body produces stiff, irregular-shaped red blood cells that are sickle shaped, in contrast to normal cells that are more round and flexible. Sickle cells tend to aggregate in clumps, blocking the flow of blood through the blood vessels, causing pain, increased risk for stroke and damage to vital organs. Blocked blood flow also means that the hemoglobin contained in red blood cells is not able to adequately transport enough oxygen from the lungs to body tissue, eventually resulting in tissue damage. Sickle cells also have a shorter lifespan, which often results in anemia. Although some patients are treated with bone marrow transplants to trigger the production of normal red blood cells, “matched” donors are only available to 5% of patients. The National Institutes of Health estimate that more than 70,000 people in the US have sickle cell anemia.
The researchers first extracted skin cells from the tails of three diseased mice and “rewound” them back to an embryonic-like state using certain viruses called retroviruses that can switch on dormant genes that are active in days-old embryos. These embryonic cells, known as induced pluripotent stem cells (iPS) for their ability to differentiate into a variety of cell types, were then modified so that the genetic defect responsible for sickle cell anemia was corrected. Because these iPS cells have been brought back to an early development stage, they can be cultivated for a specific therapeutic purpose. In this case, the iPS cells were grown in a carefully controlled culture to become blood-forming bone marrow stem cells that were reintroduced, by injection, in the mice. The new cells then helped to create a healthy blood supply, effectively correcting sickle cell anemia in the mice.
The use of iPS cells has several advantages. Since the cells originate from the patient, there is no risk of tissue rejection. Another advantage is the number of potential applications. Scientists are optimistic that iPS cells can be developed to cure several disorders such as thalassemia (a genetic disorder in which the production of hemoglobin are red blood cells are reduced), severe combined immunodeficiency disease ( a genetic disorder characterized by a severely compromised immune system) and hemophilia. “This is a platform for any one of dozens of human genetic blood diseases, not just sickle cell anemia,” said Dr. George Q. Daley, a stem cell scientist at Harvard Medical School. In addition, other single gene mutation disorders like muscular dystrophy and cystic fibrosis, may also benefit.
Another advantage, which appeals to scientists, health officials and lay persons alike, is that reprogrammed stem cell therapy completely circumvents the need to destroy human embryos. This eliminates the ethical and controversial questions associated with the use of embyonic stem cells.
Although study on iPS cells is advancing rapidly, its availability in humans is still several years away, with more testing needed to fine tune the process. “We need a delivery system that doesn’t integrate itself into the genome,” said Jacob Hanna, lead author and postdoctoral researcher at MIT. “Retroviruses can disrupt genes that should not be disrupted or activate genes that should not be activated.”
Still, researchers are optimistic. “There’s going to be this tsunami,” said Paul J. Simmons, PhD, director of the Centre for Stem Cell Biology at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at the University of Texas Health Science Center in Houston. “One would have to predict that the pace of observations made using iPS cells is going to rise exponentially.”
The study, “Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin,” was published in the December 21, 2007 issue of Science.
Sources: LA Times, December 7, 2007; MIT News online