The study, from researchers in the United States, is the first to show that induced pluripotent stem (iPS) cells, which are capable of becoming any other type of cell, can be used to model the pathology of the genetic muscle-wasting disease spinal muscular atrophy. The cells were derived from skin cells taken from a child with the disease, and are therefore genetically identical.
Prof Robin Lovell-Badge, Head of Developmental Genetics Division, MRC National Institute for Medical Research, said:
“This is an interesting paper although for several reasons there is a need for caution, indeed aspects of the work are rather preliminary.
“It is impressive how fast the iPS field is moving. This is at least the fourth paper deriving such cells from human patients suffering from a range of genetic diseases, in this case spinal muscular atrophy (SMA), and I expect we will see many more in the months to come. Because iPS cells are pluripotent and in theory can be used to obtain in the lab any cell type of the body, they can be used to study how cell defects arise and potentially search for treatments, including screening for small molecule drugs.
“As the authors say, SMA is an ideal disease to approach in this way. It is a particularly nasty disease affecting very young children, who usually die by the age of 2. However, it is not understood why specific motorneurons are so sensitive to a deficiency of SMN proteins, caused by mutations in the SMN1 gene, even though this is normally active in all cell types. While there are some useful animal models, these do not mimic the human situation well enough, and a source of human motor neurons carrying SMN1 mutations has until now been impossible to obtain.
“The authors derived iPS cells from fibroblasts from the skin of an affected child and from his unaffected mother for comparison. Using methods derived previously from work on human Embryonic Stem cells, they were able to obtain motorneurons from both these iPS cells but found that the former were defective: many did not mature properly and died in culture. However, one reason for caution is that they only looked at one iPS cell line from the child. To derive these cells requires genetic reprogramming, and we do not yet know how reproducible this is – for example, reprogramming using cloning techniques is notoriously variable. Motorneurons are very special cells and perhaps they were unlucky in that the defects seen in this case had nothing to do with the lack of SMN proteins, but were due to inappropriate expression of other genes within the cells. It is very risky to rely on a sample size of one in any experiment, and I am surprised that the authors were allowed to publish this now.
“Previous work had already identified some candidate drugs that might help boost expression of the related SMN2 gene, which could ameliorate the symptoms, thus allowing the authors a chance to test these on their cultured cells. This is another reason why SMA was an appropriate choice of a disease to study using this technology. The authors found that the drugs do indeed increase the amount of SMN protein in the iPS cells derived from the patient. This seems promising, except they did not look to see whether this rescued any of the motorneurons. If they had been rescued, then this would have validated both the use of this particular iPS cell line and the approach to screen for drugs.
“So while this represents a good start, there is much more work to do to provide understanding of this particular disease process. Moreover, even though the iPS field is moving fast, we should not be misled – there will still be all the difficult and time-consuming steps required to develop safe and efficient therapies. However, this work should provide a little cheer for all those who have to deal with SMA patients in their families or their clinic – it represents a new approach and one with considerable promise.”
Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign, said:
“Induced pluripotent stem (iPS) cells might play a role for the treatment of neuromuscular conditions, including spinal muscular atrophy (SMA) in the future, but they currently provide an immensely valuable tool to test potential drugs on a large scale in the laboratory.
“The findings published, by Allison Ebert and colleagues, are a crucial step forward in the evaluation of this tool because they show for the first time that iPS cells derived from the skin cells of a child with SMA retain their characteristics when induced to become nerve cells. We hope this technique will speed up the search for a treatment for SMA so that one day parents will not lose their very young children to this devastating disease.”