Genetics and stem cells

New way of treating gene defects explored

Doctors have made a “breakthrough in repairing genetic defects”, The Guardian reported.

This news comes after researchers conducted a small trial that tested genetic engineering as a treatment for haemophilia B in mice. In humans, haemophilia B is caused by a genetic fault that interferes with the production of a protein that normally aids blood clotting. In this study, researchers introduced a genetic “toolkit” into living mice to target a faulty gene involved in haemophilia and to replace it with a fully functioning version. The study found that after treatment, the animals’ blood clotted in 44 seconds compared to more than a minute in untreated mice with haemophilia.

This was a small “proof of concept” study and further studies are required to confirm the findings of this exploratory research. The efficiency of this “genetic editing” technique was also limited, with success in only 3–7% of cases.

The early stage of this research means it is not yet clear whether these techniques in animals could eventually be used in humans. There is often a long time between this type of study in animals and the development of a therapeutic cure in humans, but the study provides an important first step towards that goal.

Where did the story come from?

The study was a collaboration between researchers from the Children’s Hospital Philadelphia and other institutions based in Philadelphia and California in the US. The research was funded by the US National Institutes of Health and the Howard Hughes Medical Institute.

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

While_ The Guardian_ ’s article mainly focused on the potential human implications of the research, its coverage was balanced and clearly stated that the study was in mice and that the technique was inefficient.

What kind of research was this?

This animal study tested whether it was possible to use a gene repair “toolkit” to correct a genetic defect in living mice. The authors state that similar gene repair techniques have been shown to be effective in correcting defects in cells by removing them from an animal, genetically modifying them in a dish in a laboratory, and returning them to the animal. This is not suitable for many diseases, where the affected cells cannot be easily removed from the body and returned. This study developed and tested a method that might be used to correct genetic problems within the body, without the need to remove cells.

The main limitation of this study type is that researchers cannot be certain whether the findings in animals will apply to people. Also, before the technique could be tested in human trials, the researchers will need to ensure that it would be safe enough for use in humans.

What did the research involve?

This study used a genetically engineered mouse model of the human disease haemophilia B. Haemophilia B is caused by a deficiency in a blood-clotting factor (factor IX) that is normally produced by the liver. The condition is caused by errors, or mutations, in the F9 gene.

Mice were bred to carry the human F9 gene. The version of the gene they carried included a mutation that stops factor IX from being produced, leading to haemophilia B.

The researchers then engineered a genetic toolkit that was designed to cut the mutated F9 gene out of the mouse DNA and introduce a working version of the gene in its place. The toolkit introduced into the mice used enzymes, called zinc finger nucleases (ZFN), that could produce a targeted “cut” in the DNA near the start of the mutated F9 gene. The type of cut produced stimulates the body’s own natural DNA repair mechanisms. A separate part of the genetic toolkit included a template for the normal (non-mutated) version of the human F9 gene, which would allow the cell to produce a fully functioning version of the factor IX protein. This template was designed in such a way as to allow the cell to incorporate this normal version of the F9 gene into the cut region of the DNA during the repair process.

The researchers used a genetically modified virus to deliver their toolkit to the liver cells in order to correct the genetic mutation and allow the liver to produce factor IX normally.

The genetic toolkit was initially introduced into human liver cells grown in the laboratory to see if it functioned as expected. The researchers then injected it into living mice carrying the mutated F9 gene to test how well it specifically targeted the liver cells. They also assessed how much blood-clotting factor was produced as a result of the genetic fix by analysing blood samples and by removing and analysing the mice’s livers. Finally, they compared the time it took for the blood to clot in treated and untreated haemophilic mice.

What were the basic results?

In two types of laboratory-grown liver cells, the genetic toolkit was successfully able to cut the existing DNA and paste the normal (non-mutated) version of the human F9 gene into the correct region. This process occurred in 17–18% of mutated DNA. When testing the toolkit in mice, the researchers found that 1–3% of the mutated genes in the liver tissue had been repaired by the genetic toolkit.

Overall, they found that their technique produced a 3–7% increase in production of clotting factor IX circulating in the blood of the mice, and that the amount of circulating blood-clotting factor correlated with the level of success in repairing the mutant gene.

After the mice had received treatment, their blood clotted in 44 seconds compared to more than a minute for the mice with untreated haemophilia. However, only five normal mice were compared to 12 treated mice.

How did the researchers interpret the results?

The authors reported that their new technique is “sufficient to restore haemostasis (normal blood clotting control) in a mouse model of haemophilia B, thus demonstrating genome editing in an animal model of a disease”. They also reported that the level of genetic editing achieved in this experiment was “clinically meaningful”.


This research demonstrates that a genome-editing technique can be used to correct a genetic defect in living animals, and that this treatment can improve a clinical defect, in this case blood-clotting time in haemophilic mice. This was achieved without the need to remove and genetically manipulate cells, a step that has been necessary when using previously researched techniques.

This study was performed in a small number of mice, so the results will need to be reproduced in more animals to confirm the findings and to improve the efficiency of the technique, which is currently low. It is not yet certain whether these findings in animals can be applied to people. Research will be needed to ensure that such a technique would be safe enough for use in humans before it could be tested for the treatment of human diseases. In addition, research will be needed to determine whether the technique might apply to other genetic conditions, and whether DNA can be cut at the site of other faulty genes and that the technique can target organs other than the liver.

It often a takes a long time for proof of concept research in animals to be developed into a therapy for humans, but this study is an important first step in that process.

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