Skin cell to liver cell shows promise for genetic liver disease

By Dr. Ananya Mandal, MDOct 13 2011

In a new scientific breakthrough, researchers have taken skin cells from a patient with liver disease and turned them into replacement liver cells. Although the procedure is years before it can be used in humans, but if approved, it could launch a new era of personalized therapies for serious genetic disorders.

It is known that nearly 30,000 people Britain carry a genetic defect that causes antitrypsin deficiency, a disease that can only be cured by a liver transplant. The operation requires a suitable donor organ and costs around £500,000, with drugs to prevent rejection by the immune system adding more than £20,000 a year to medical costs. The genetic glitch that causes the disease makes liver cells produce faulty versions of a protein. The normal protein circulates in the blood and protects the body's tissues and organs from routine damage, but in people with antitrypsin deficiency, malformed proteins accumulate in the liver. Over time, the condition causes cirrhotic liver disease and leaves other organs vulnerable to damage. Most at risk are the lungs, and many patients develop progressive emphysema as a secondary condition.

This method of treating a patient with their own cells removes the need for anti-rejection drugs, reduces the burden on strained transplant services and is likely to be cheaper, the scientists behind the technique believe.

“The disease affects very young people, including babies, and there are not always suitable donors for many of these individuals,” said Allan Bradley, the former director at the Wellcome Trust's Sanger Institute in Cambridge. “These are early steps, but if this technology can be taken into treatment, it will offer great possible benefits for patients.”

Writing in the journal Nature, the team, led by researchers at the Sanger Institute, describes how they turned to the rapidly advancing field of stem cell science to find a new way to tackle the disease. They found a procedure that took months from start to finish and involved several steps that drew on recently developed genetic techniques.

In the new therapy, researchers harvested stem cells using a skin biopsy from a patient with mutant alpha1-antitrypsin. They snipped the cell's genome and reinserted a correct version of the gene using the DNA transporter piggyBac. They resulted in fresh liver cells with no trace of genetic manipulation.

Embryonic stem cells are controversial because they derive from human embryos. However, induced pluripotent stem cells (iPS), like the cells used in this study, originate in a lab from the patient's own skin or blood cells. However, scientists have questioned their capability of providing effective therapy. Co-author David Lomas, deputy director of the Cambridge Institute for Medical Research said his study suggests that iPS might someday be a viable option for treating liver disease.

“If we can use a patient's own skins cells to produce liver cells that we can put back into the patient, we may prevent the future need for transplantation,” said Lomas. Scientists elsewhere are now expected to develop the procedure to treat other genetic conditions, including those that require the correction of several mutations at once.

“What we are thinking about now is how we can take this through to humans, accepting that safety is paramount. The beauty of our approach is that we can make the genetic correction and we can do it cleanly,” said Lomas.

“This is a very impressive piece of work,” said Robin Lovell-Badge, head of genetics at the MRC's National Institute for Medical Research in London. “There are worries that the reprogramming process to derive iPS cells is not always accurate or complete and that it can lead to mutations and DNA abnormalities. They found that some mutations have crept in due to the reprogramming and cell culture, but by carrying out a robust screen, they could select the least affected cell lines. So this is still a concern, but they show that it is perhaps a manageable one…The methods developed in this paper should be useful to correct mutations in other human genes, although the accuracy will need to be checked in each case,” he added.

The researchers said it could be another five to 10 years before full clinical trials of the technique could be run using patients with liver disease.