First Successful Use of Genome Editing In Living Animals Cures Hemophilia In Mice

Lab Mouse

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A targeted snip through DNA's double helix can take out a mutated gene that causes hemophilia, curing mice of the disease, a new study found. It's the first study to use this form of genome editing in a living animal, and it could have implications for genetic treatment of other diseases, notably AIDS.

Scientists say the research is a major step forward for gene therapy, which has long promised to cure disease by editing genetic sequences.

The therapy is based on enzymes called zinc-finger nucleases, which serve as a sort of genetic scissors. The enzymes are engineered to match a specific gene location on a chromosome, where they snip through DNA's double helix.

In this case, researchers led by Katherine A. High, a hematologist and gene therapy expert at The Children's Hospital of Philadelphia, used ZFN proteins that were engineered to snip through the location of a genetic mutation that causes hemophilia. Hemophiliacs lack a blood-clotting factor made by the liver that helps stanch bleeding, so their blood cannot clot, meaning minor injuries can be life-threatening.

High and colleagues had to take another step in their research, because hemophilic mice have a different genetic mutation than humans. They engineered mice to express the faulty human sequence, located on the F9 gene, and they designed ZFNs to cut through it. Then they engineered a virus that targets the liver (where the blood clotting factor is made) to carry the normal, unmutated version of F9.

As a result, the mutated section was removed, and the unmutated gene was inserted instead. Then the DNA molecule is stimulated to repair itself, sewing the new gene in place.

This is an improvement over other genetic editing techniques that use viruses to cut and paste the new genes. Although they have been shown to work, viral therapy has some inherent problems, including unpredictable chromosomal insertion, which can induce unwanted mutations. But the ZFN is designed to home in on a precise location of mutated DNA.

After this treatment, the animals' blood clotted in 44 seconds, compared with more than a minute for hemophiliac mice, according to Nature.

The study shows that zinc finger proteins and replacement genes can be used to induce changes in living animals, which is promising for a wide range of therapies. For instance, other researchers are using ZFNs to disrupt a gene that makes a receptor used by the AIDS virus, as the New York Times reports. People without that gene, CCR5, are naturally immune to HIV.

The mouse study is reported in this week's issue of the journal Nature.