Published online 22 December 2008 | Nature | doi:10.1038/news.2008.1323


Reprogrammed skin cells provide testing ground for new drugs

Induced pluripotent stem cells pass key milestone.

cellsMotor neurons (red) created from skin cells could provide a better model for studying disease.Allison Ebert

Skin cells from a patient with a genetic disease called spinal muscular atrophy (SMA) have been reprogrammed into stem cells that can be used as a model of the disease. The research marks an important milestone in creating and using stem cells to understand disease processes and screen drugs.

SMA is an inherited disease that causes the degeneration of motor neurons, leading to muscle weakness, paralysis and often death. Patients with the most severe form of SMA, caused by mutations in the survival motor neuron 1 gene (SMN1), typically die before they are two years old.

There are no licensed drugs to treat SMA, in part because the disease has not been recreated in laboratory animals in a reliable way. "The animal models are pretty useless, to be honest," says Clive Svendsen, a cell biologist from the Waisman Center at the University of Wisconsin, Madison.

To build an improved model, Svendsen and his colleagues first took tissue-forming fibroblast cells from the skin of a deceased SMA patient. Then they reprogrammed these cells to become so-called induced pluripotent stem (iPS) cells, which behave just like the embryonic stem cells that are the progenitors of all the body's different cell types. Finally, the scientists developed a new method to turn those iPS cells into large numbers of motor neurons, the cell type affected in SMA.

These redifferentiated motor neurons express lower levels of SMN1, just like the motor neurons in SMA patients, the authors report in Nature1.

Although researchers have previously generated and then redifferentiated iPS cells from patients with other diseases23, this is the first time they have shown that these redifferentiated cells have similar characteristics to diseased cells.

"This is certainly the first of many iPS cell-derived cell lines that will play a major role in future drug discovery," says Chris Mason, who studies stem cells at University College London, UK.

Beautiful example

The researchers also found that the reprogrammed cells could be used to assess the effects of two experimental drugs for SMA — valproic acid and tobramycin.

Scientists already knew that in humans a gene called SMN2 can compensate for the SMN1 mutations seen in SMA, and now Svendsen's team has shown that the experimental drugs can help that process. "The SMN2 gene just works a little bit harder when these drugs are given," says Svendsen, adding that the drugs may help to relieve disease symptoms.

Not only does this experiment show that iPS technology can be used to model SMA, says Svendsen, it also provides proof-of-principle that reprogrammed cells can be used to test drugs.

It's a "beautiful example" of using stem cells to develop a model of a disease, says George Daley, who works with stem cells at the Harvard Stem Cell Institute. The next stage, he adds, is to scale up production of these cells so that they can be used efficiently to screen large libraries of compounds — a step that is far from trivial, he cautions.

However, Svendsen says that this work is already underway and hopes that screening technology will be in place "within a year or two". 

  • References

    1. Ebert, A. D. et al. Nature doi:10.1038/nature07677 (2008).
    2. Dimos, J. T et al. Science 321, 1218–1221 (2008).
    3. Park, I. H. et al. Cell 134, 877–886 (2008).
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