US scientists have shown that the genetic fault underlying sickle cell disease can be corrected in embryonic stem cells (ES cell) derived from mouse embryos with the disorder. The team, based at the University of California, San Francisco (UCSF), derived ES cell lines from affected embryos, and managed to replace the mutated gene with a working copy in one of the cell lines. They then used the corrected ES cells to grow healthy blood cells in the laboratory. The research, published early online in the journal Proceedings of the National Academy of Sciences, offers hope for a potential new treatment for sickle cell disease, and also beta-thalassaemia - another inherited blood disorder.
Sickle cell disease causes chronic anaemia and bouts of severe chest and joint pain. It is caused by an altered form of the oxygen-carrying protein haemoglobin, which tends to join together in long strands when it is not carrying oxygen. These strands of altered haemoglobin give the red blood cells their 'sickle' shape, which in turn causes the chest and joint pain, and can also lead to serious complications such as stroke. The disorder affects people who inherit two mutated versions of the beta globin gene, which makes part of the haemoglobin protein. Although some drugs can reduce the severity of the condition, the only cure is a bone marrow or umbilical cord blood transplant from a genetically matched donor.
The UCSF scientists had previously bred genetically altered mice affected by sickle cell disease. In the latest study, they used these animals to create mouse embryos in the laboratory that had two copies of the mutated human beta globin gene. They derived ES cells from these embryos, and used one of the resulting cell lines for further experiments. The team used a 'gene targeting' technique to replace one of the mutated beta globin genes with a working copy. They then coaxed these corrected ES cells to grow into blood stem cells, which were healthy - showing that the inserted beta globin gene was making normal haemoglobin, and masking the effects of the mutated gene.
The researchers say it would be possible to use the corrected ES cells to cure mice with sickle cell disease. They also say that the technique could potentially be applied to people affected by inherited blood disorders, using nuclear transfer (so-called therapeutic cloning) to create blood cells genetically matched to patients. However, following the recent discovery that all the cloned human ES cell-lines reported by a South Korean team are in fact fakes, it remains to be seen whether this approach will be feasible. Although other scientists have managed to create cloned human embryos, none have survived long enough for stem cell lines to be derived from them.