Clive Svendsen1

Results of unregulated stem cell transplant were predictable and avoidable

(This commentary provides an expert perspective to an article published in PLoS Medicine, which has been reported in Nature and Nature Reports Stem Cells.)

The study by Amariglio et al. describes a stem cell transplant attempt in a child with ataxia telangiectasia, a rare genetic disease that leads to poor coordination and dilation of blood vessels1. These patients also have weakened immune systems and are more prone to cancer.

There has been a growing demand that stem cell cures be developed for many diseases. This has led to US and European families feeling that not enough is being done, and an alarming number of patients are being drawn to overseas clinics for costly but poorly defined stem cell treatments.

In this case, the parents of the child with ataxia telangiectasia took him to Russia for a stem cell treatment — presumably hoping that the foetal stem cells would somehow reverse the disease process. However, there is no published evidence of this occurring in animal models, and the paper presents no clear rationale of how it might have worked had it been successful.

The Russian surgeons collected eight-week-old foetal brain tissue (presumably from elective abortions). The tissue, from an undefined brain region, was then removed and expanded in culture for 12–16 days. Between 50 and 100 million cells were then injected into the white matter of the patient's cerebellum by direct injection and into the spinal cord using a lumbar puncture technique. Compared with other trials in which cells derived from foetal tissues have been transplanted into animals or patients, this is an enormous number of cells (orders of magnitude greater than anything previously reported). None of the surgical methods were described in any detail. Apparently the child returned to Russia for three treatments over a period of a few years, tripling the total number of cells received up to 300 million.

The result was entirely predictable based on the current knowledge of foetal tissue stem cell growth and differentiation following transplantation into animal models. A tumour is most simply defined as a lump of growing tissue that is either benign or cancerous. The cells began to form lumps of growing tissue, or tumours, that had both neural and glial cells. This is exactly what these cells are designed to do by nature. Taken at a very early stage of development perhaps from a region that is destined to make billions of cells (the human cortex), the foetal cells tried to make a mini-brain in the spinal cord. Although it was difficult to establish from the limited data in this report, there were no overt signs of excessive cell growth, perivascular cuffing or chromosomal abnormalities within the growing cells, all of which would suggest a cancerous tumour. There was simply a lump of apparently benign cells that contained healthy neurons and astrocytes near the area of the injection. This is in fact very encouraging for future clinical trials in which the correct administration and dose of cells could be established.

The conclusion from this report is that injecting millions of human foetal cells into the brain or spinal cord will result in a tissue mass that continues to develop over time — just like a developing human brain would in the foetus. It, along with data from preclinical animal studies, tells us that we should carefully control the number of cells that we transplant, as any growing mass in a restricted region of the brain or spinal cord is potentially dangerous. The paper also shows that repeatedly injecting hundreds of millions of stem cells is not going to make a patient better, and it raises a number of very worrying concerns over regulations and rationale for stem cell therapies abroad that are not FDA approved.

This is a crucial paper because it highlights the importance of careful FDA monitoring for any stem cell clinical trials in the United States. This will protect patients and their families from poorly designed, expensive, naive and dangerous clinical trials such as the one described in this report.

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Reference
1. Amariglio, N. et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia     telangiectasia patient. PLoS Med. 6, e1000029 (2009); doi:10.1371/journal.pmed.1000029.
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Author affiliations
1. Clive Svendsen is professor of anatomy and neurology and Co-Director of the Stem Cell and      Regenerative Medicine Center at the University of Wisconsin at Madison.

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