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Brian Madeux, who has Hunter syndrome, has received a treatment aimed at editing the genome of his liver cells. 

AP Photo/Eric Risberg

A human has been injected with gene-editing tools to cure his disabling disease. Here’s what you need to know

For the first time, researchers have infused a person’s blood with gene-editing tools, aiming to treat his severe inherited disease, The Associated Press (AP) reported today. The 44-year-old patient has a rare metabolic disorder called Hunter syndrome. But how big is the advance—and what does it mean for using hot new technologies such as CRISPR to help people with other genetic diseases?

How does the treatment work?

Hunter syndrome results from a mutation in a gene for an enzyme that cells need to break down certain sugars. When the enzyme is defective or missing, the sugars build up and can cause developmental delays, organ problems, brain damage, and early death. Brian Madeux, the first patient in what will be a small clinical trial has a mild form of the disease, but nevertheless has had more than two dozen operations as a result, AP reports.

Someday, researchers may be able to use gene editing to repair the flawed gene in cells that causes diseases like Hunter syndrome. However, that’s not the goal of the trial, sponsored by Sangamo Therapeutics, a biotech company based in Richmond, California. Instead, the company inserts a replacement copy of the gene, using gene editing to snip the DNA helix of liver cells in a specific place near the promotor, or on-off switch, for the gene for a protein called albumin. The cells fix the damage by inserting the DNA for the new gene, supplied by the researchers along with the gene editor’s DNA scissors, and the gene’s activity is then controlled by the powerful albumin promotor. The idea is to turn these modified liver cells into a factory for making the enzyme missing in Hunter syndrome.

Sangamo’s targeted approach, known as “safe harbor,” should avoid the risks of using traditional gene therapy to alter a cell's genome, which pastes in the new gene at a random place in the genome and can potentially turn on a cancer gene. And because the body doesn’t need much of the enzyme, modifying just a small fraction of the liver’s cells should be enough to treat the disease.

Although Hunter syndrome patients often receive weekly infusions of the missing enzyme, their blood levels drop within a day, says Sangamo CEO Sandy Macrae. The hope is that the one-time gene-editing treatment—given as a 3-hour intravenous infusion—will allow the liver to keep making the enzyme at a steady rate for years. There is a caveat, however: The enzyme Hunter patients now receive does not cross the blood-brain barrier, the tight network of cells that protects the brain from pathogens, and the livermade enzyme produced by the gene edit may not either. So the new treatment may not stop the brain damage that can occur in Hunter syndrome.

Is this the first gene-edited human?

Not quite. The trial is using a form of DNA scissors called zinc finger nucleases (ZFNs). Like the newer gene-editing technology CRISPR, ZFNs can cut both strands of the genome’s double DNA helix at a specific location. In trials several years ago, Sangamo used ZFNs to protect patients from HIV by harvesting their blood cells, disrupting a gene in them while growing in culture, and then transfusing the cells back into the patients.

However, this is the first time ZFNs have been used directly to modify DNA in living patients—so-called in vivo gene editing. This is more complicated than editing cell’s DNA in a lab dish. For one thing, researchers must use a viral vector to ferry DNA encoding the ZFNs and the new gene into the liver cells. Although this virus, called adeno-associated virus, is widely used in gene therapy and is considered safe, it can trigger a potentially dangerous immune response in some patients—usually managed with steroids.

And in vivo gene editing poses additional risks. Similar to the problem of traditional gene therapy hitting the wrong spot, ZFNs could make cuts in places where they weren’t supposed to and turn on a cancer gene. Compounding this risk, the liver cells that now contain the DNA for ZFNs will keep making the nucleases for perhaps years, even though they are no longer needed to guide the new gene to its spot in the genome. 

Sangamo’s Macrae says the company is confident that off-target cutting will be rare and would mainly occur in nonfunctioning stretches of DNA between genes. Virologist Marie-Louise Hammarskjold, who sat on a National Institutes of Health panel that approved the strategy, agrees that the safety data are convincing. “They had pretty good evidence, based on animal and cell culture experiments, that the off-target effects wouldn't be such a high risk that [the trial] was not worth trying,” says Hammarskjold, who is at the University of Virginia School of Medicine in Charlottesville.

Investigators will check for off-target effects by taking liver biopsies from some patients and looking for DNA changes, Macrae says. Even if the tests don’t find anything of concern, however, they could miss a cancerous cell somewhere in a patient’s liver that years from now will grow into a tumor, cautions gene therapy researcher Mark Kay of Stanford University in Palo Alto, California.

What’s next?

Sangamo is also testing the liver-factory gene treatment in trials now getting underway for the blood-clotting disorder hemophilia B and another metabolic disease, Hurler syndrome. “Once you show that this works and there are no horrible side effects, you could try it with many other diseases” by swapping out the inserted gene, Hammarskjold says. “That’s the big hope in this case. You don't have to reinvent the wheel every time.”