Sickle Cell Anemia treated using Reprogrammed Skin Cells in Mice

Scientists in the US have used a recently proven stem cell technology based on reprogramming skin cells to make them act like embryonic stem cells to treat sickle cell anemia in mice. Although proved in principle, the technique is not safe to use in humans and there are some significant hurdles to overcome before it is.

The study is published in the December 6th online issue of the journal Science and was carried out by Tim Townes of the University of Alabama, Birmingham, and colleagues.

Last month, another group of scientists showed it was possible to reprogram human fibroblast skin cells into an induced pluripotent (iPS) or embryonic stem-cell like state by inserting four transcription factors. This opened a new avenue for obtaining the benefits of customized embryonic stem cells without the ethical problems of creating and destroying embryos.

However, the therapeutic potential of such iPS technology had not yet been tested.

In this new study, Townes and colleagues used mice with sickle cell anemia, a type of blood disorder caused by one faulty gene.

Blood cells is a good place to start because they are easier to replace than tissue cells. Sickle cell anemia causes red blood cells to curve which impedes their transit in blood vessels.

Stem cell researcher and co-author of the paper, Rudolf Jaenisch of the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, both in Cambridge, said that mice with sickle cell anemia show many of the human symptoms which makes them good subjects to test the potential therapeutic value of iPS cells.

Townes, Jaenisch and colleagues took skin cells from the tails of mice with sickle cell anemia and inserted the four transcription factors to convert them into iPS cells. Then they inserted a corrected hemoglobin gene into the iPS cells and encouraged them to develop into a type of stem cell that produces blood cells.

After exposing the mice to radiation to kill their own blood stem cells, the researchers injected them with the new blood stem cells containing the corrected hemoglobin gene. Within a few weeks the new stem cells were producing new mature blood cells and the symptoms of sickle cell anemia were significantly reduced.

Townes said he and Jaenisch had previously tried to use a cloning method to make corrected stem cells, also called nuclear transfer, where the nucleus of an egg is destroyed and replaced with the desired DNA, but the experiments failed because the method was not efficient enough. He said the iPS method was "amazingly efficient".

An article in ScienceNOW reported that Jose Cibelli of Michigan State University in East Lansing called this study an "important step forward". The results are impressive, said Cibelli but:

"If they do not have therapeutic value, they will be far from getting to the point of replacing the whole idea of therapeutic cloning."

What needs to happen next, said Cibelli, is for scientists to find reliable ways to make a range of useful cell types from these cells and to overcome the problem posed by undifferentiated cells that can cause tumors.

Other experiments have shown that if some of the cells do not differentiate, they can start to produce undesired cells and cause cancer. But in this study the mice did not show signs of this after 12 weeks. However, this is not long enough to prove the method is safe, said Townes, and much longer term experiments are needed before iPS techniques can be trialled in humans.

Townes and colleagues concluded that:

"Our results provide proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy."

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