Genetics and stem cells

Stem cells 'could fight genetic diseases'

Research has combined stem cell technology and precision gene therapy for the first time, BBC News has today reported. The broadcaster said that new research marrying the two disciplines means patients with a genetic disease could one day be treated with their own cells.

In the study researchers used cells from people with a genetic liver condition to generate a type of stem cell called ‘induced pluripotent stem cells’ (iPSC), which have the ability to transform into other types of cells, including liver cells.

These stem cells were not suitable for treating the disease because they still carried the genetic mutation that causes the condition. However, the researchers then applied genetic technology to target and remove the genetic sequence carrying the mutation, replacing it with a functioning sequence. The resultant stem cells were then grown into liver cells and tested in both laboratory and animal models, where they were found to behave like healthy liver cells.

The use of genetic technology to precisely remove genetic mutations is an exciting step forward in developing personalised stem cells that may be suitable for treating human disease. The results also suggest ways in overcoming some of the hurdles that stem cell research has previously faced.

This complex, cutting-edge technology is still in the early stages of development, however, and will require significantly more research before it could be used in clinical trials in people.

Where did the story come from?

The study was carried out by researchers from the Wellcome Trust Sanger Institute, the University of Cambridge, Institut Pasteur in France, Instituto de Biomedicina y Biotecnología de Cantabria in Spain, Sangamo BioSciences in the US, Università di Roma in Italy, and DNAVEC Corporation in Japan. The research was funded by the Wellcome Trust.

The study was published in the peer-reviewed journal Nature.

News sources generally reported the story accurately, mentioning the early nature of the research and the need for further studies to confirm the safety of the technique.

What kind of research was this?

This was a laboratory-based study with an animal model component. It looked at whether a method could be developed for combining techniques for correcting genetic mutations and generating stem cells from patients’ own cells that might have applications in treating inherited disease. This is reported to be the first study to attempt to use this type of approach.

While there have been numerous studies looking at these disciplines separately, this is reported to be the first study to assess a combination of the two in human tissue.

Stem cell therapy is based on the idea that we might be able to harness the properties of stem cells, special types of cells that can produce new cells indefinitely and also develop into other types of cell.

This new study was broadly based on the principle that cells could be extracted from patients with mutations and turned into stem cells in the laboratory, which would then have their mutations corrected using special genetic techniques. If such techniques could be perfected, these corrected stem cells could theoretically be grown into tissue in a lab and reinserted into a patient, providing them with tissue that would now function normally.

In the current study, the researchers studied a specific genetic mutation that causes an illness called α1-antitrypsin deficiency. This mutation in question is a single incorrect ‘letter’ in the DNA sequence (called a ‘point mutation’ as it affects only one point in the DNA). It causes faulty production of the α1-antitrypsin protein.

This mutation can lead to liver cirrhosis (scarring of the liver tissue) and eventually liver failure. People with liver failure will need a liver transplant, but it is not always possible to find a matching donor, and even when a transplant can be performed, the recipient will have to take drugs to suppress their immune system. If new liver tissue lacking the mutation could be grown from the patient’s own cells, this could reduce the need for donors and the risk of the tissue being rejected.

Laboratory and animal research is commonly used in the early stages of developing such new techniques. This is because new technologies must undergo proof-of-principle studies and fine tuning before they are suitable for safety tests in humans.

What did the research involve?

The study used gene targeting techniques to cut out the mutated section of the DNA and replace it with the correct gene sequence. However, the researchers say that current techniques to target and replace mutations are not precise enough, as they can leave behind unwanted sections of genetic code. This can lead to unexpected effects.

Instead, they used methods that were capable of correcting a single mutation within stem cells without leaving behind any other unwanted sequences in the genetic code. To assess their technique they tested it in stem cells from mice to make sure it would work correctly.

Stem cells are capable of dividing indefinitely and of developing into any different type of cell in the body. Once cells fully develop they no longer have this capability, but researchers have created techniques that allow them to ‘re-programme’ fully developed adult cells in the laboratory to become stem cells again. Stem cells produced in this way are called ‘induced pluripotent stem cells’ (iPSCs), and these were the types of stem cells used in this study.

Once they showed that their technique worked in mice, the researchers then produced iPSCs from the patients’ own skin cells in the laboratory. They then used the gene targeting techniques they had developed to replace the α1-antitrypsin mutation with the correct genetic sequence. As the patients included in this study had inherited two copies of the mutation (one from each parent), the researchers checked whether the technique had fixed both copies of the gene in these extracted cells.

Previous research has shown that there are problems with growing stem cells in a laboratory setting. Cells grown in this way are prone to developing genetic mutations and may not be suitable for use in clinical therapy. To test whether or not the iPSCs developed in this study were similarly prone to mutations, the researchers compared their genetic sequence to that of the cells originally used to generate the iPSCs.

Once the researchers had confirmed that their technique resulted in iPSCs with the correct genetic code, they checked that the genetic modification had not affected their ability to develop into liver-like cells, as unmodified stem cells would. They then used an animal model to see if these liver-like cells would behave like healthy liver cells, transplanting the cells into the livers of mice and testing the livers 14 days later. They assessed whether or not the injected cells showed further growth and integrated into the organ.

What were the basic results?

When the researchers tested the genetic sequence of their cells, they found that the mutation had been successfully corrected in both chromosomes in a small number of the iPSCs from three patients. These genetically corrected iPSCs were still able to develop into different types of cells in the laboratory.

When the researchers compared the genetic sequences of the iPSCs with that of the original patients’ donor cells, they found that the genetic sequence in cells from two of the three patients differed from the original sequence - in other words, they carried unintentional mutations. Cells from the third patient, however, maintained their original genetic sequence (other than the corrected mutation). These cells were used in the last part of the experiment.

When these iPSCs were further developed into liver-like cells, the researchers found that in the lab, the cells behaved like healthy cells in the body would. They stored glycogen (a molecule made from glucose involved in energy storage), they absorbed cholesterol, and released proteins as expected. They also did not produce the faulty α1-antitrypsin protein but instead produced and released the normal α1-antitrypsin protein as healthy liver cells would.

When they transplanted these cells into mouse livers, the researchers found that the transplanted cells had integrated into the animals’ livers, and begun to produce and release human proteins as they had in the lab.

How did the researchers interpret the results?

The researchers conclude that their technique ‘provides a new method for rapid and clean correction of a point mutation in human iPSCs,’ and that this method does not affect their basic characteristics. They add that the resultant iPSCs can develop into liver cells both genetically and functionally normal.


This is an exciting and innovative development in the exploration of the potential for stem cell therapy. The researchers say this is the first time patient-specific iPSCs have had their genetic mutation corrected and been used to create a target cell type that could potentially be used in the future to treat their genetic disease (α1-antitrypsin deficiency in this study).

They go on to add that the demonstrated normal functioning of the derived liver cells strongly supports the potential use of these techniques to make cells that could be used to treat α1-antitrypsin deficiency or other diseases that result from one-letter mutations in a person’s genetic code.

The authors do raise some problems with the research. They point out that some of the iPSCs they grew in the laboratory did develop unintended genetic mutations that may make them unsuitable for therapeutic use. They say, however, that not all of the iPSCs had such mutations, and that careful screening of the cells could lead to the development of cell lines that are safe for use in humans.

The researchers add that their approach may be suitable for providing patient-specific therapy for genetic disorders like α1-antitrypsin deficiency, but that further research is needed to confirm the safety of such an approach.

It is worth bearing in mind that this research is at a very early stage, and that the current research aimed simply to develop these techniques. The technology will need to be further developed and studied before studies in humans could be contemplated. The long-term effects and functioning of the cells is not yet known, and researchers will need to ensure they continue to function normally later on.

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