Doctors make breakthrough in repairing genetic defects

Genome editing may be applied to wide range of diseases affecting humans after successful treatment of mice

Doctors have treated a life-threatening blood disease by repairing flaws in the genetic code of a living animal, the first time such an ambitious feat has been achieved.

The work raises the prospect of powerful new therapies that can target and repair the genetic defects behind a wide range of human diseases that cannot be tackled with modern medicines.

The new technique, called genome editing, holds particular promise for a group of illnesses that run in families and are caused by faults in genes that underpin the healthy working of the immune system, bone marrow and liver.

To demonstrate the therapy, researchers treated mice that were bred to develop haemophilia B, an inherited bleeding disorder that destroys the body's ability to form blood clots.

Normally, when the body suffers a cut or graze, proteins called clotting factors combine with platelet cells in the blood to make it sticky and form a clot that stops any bleeding.

But people born with haemophilia B carry a defect in a gene that makes clotting proteins, leaving them vulnerable to excessive bleeding, even when they have not sustained an injury.

About one in 30,000 boys are born with haemophilia B which, at its most severe, requires patients to have frequent infusions of blood clotting factors to prevent spontaneous haemorrhages.

In a report in the journal Nature, a team led by Katherine High at the Children's Hospital of Philadelphia describes how genome editing reversed haemophilia B in mice, restoring their blood clotting times to near-normal without causing any apparent side-effects.

High, the director of the Centre for Cellular and Molecular Therapeutics at the hospital, told the Guardian that the work showed genome editing could achieve "clinically meaningful results" in living animals.

The complexity of the treatment reflects the exquisite molecular choreography that scientists can now achieve with modern genetic technology.

In the first stage of the therapy, the mice were injected with enzymes hidden in harmless virus shells that find their way to the liver where blood clotting proteins are made.

Once there, the viruses smuggle the enzymes into liver cells, where they home in on the specific gene sequence that is defective in haemophilia B. Having arrived at their target, the enzymes slice through the faulty gene, causing the cell to launch an emergency repair effort.

At this point, the second stage of the therapy swings into action. Injected with the enzymes are DNA templates of the healthy blood clotting gene. These feed into the cell's repair machinery and, instead of simply fixing the sliced gene, a new, working copy is created.

High's team found the technique was inefficient and raised the level of the clotting protein, called factor 9, only marginally, to about 5% of normal levels, but this was enough to have a dramatic impact on the animals' health.

"If you have 5% of factor 9, you will have mild haemophilia instead of severe haemophilia and the difference is huge. People with mild haemophilia usually only bleed if they are in surgery or suffer a trauma," High said.

The work has been seen as a welcome breakthrough in a field that has struggled to deliver on the promise many scientists believe it holds.

Waseem Qasim, who works on gene therapies at the Institute of Child Health in London, said: "The concept of gene therapy has been around for 25 years or so and we are pretty crude at it; we are basically adding copies of genes that are defective. But what they have done is insert a corrected copy of the gene exactly where it should be, and that means it is properly controlled and switched on and off as it should be.

"This has really been the holy grail for these kinds of therapies and to see that someone has got this to work in a living animal is very impressive."

Because genome editing targets a very specific region of DNA, it should avoid the problems that befell some early gene therapy trials, where genes delivered to the wrong part of a patient's genome triggered leukaemia and other cancers.

Simon Waddington, a gene therapy researcher at University College London said: "The big thing is avoiding random integration of the gene, because there is always the concern about causing leukaemia or another type of cancer. The more site-specific integration you can get, the less risk there is of causing unknown damage to the genome."

A similar technique has been used by scientists to make genetic changes to cells in a dish. In an ongoing clinical trial, the US company Sangamo, with whom High collaborates, is using a gene-slicing technique to alter immune cells in HIV patients, making them resistant to the virus.


Ian Sample, science correspondent

The GuardianTramp

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