A therapy that edits genes directly in the human body might be safe, suggest early findings from the first trial to test the approach.

Researchers from Sangamo Therapeutics in Richmond, California, designed enzymes to correct an error in the genome of people with a rare genetic disease called Hunter syndrome, who cannot break down some complex sugars. The scientists used a virus to deliver these gene-editing enzymes into the cells of patients.

The company presented the results on 5 September at the annual meeting of the Society for the Study of Inborn Errors of Metabolism in Athens. The data on the efficacy of the approach come from just four people enrolled in the study for 16 weeks. Although there are some signs that the treatment reduced levels of a biochemical marker used to assess the severity of Hunter syndrome, it is too soon to know whether the therapy worked.

Hunter syndrome is caused by mutations that disable an enzyme called iduronate-2-sulfatase (IDS), which is responsible for breaking down certain complex sugars in the body. When those sugars accumulate, they can damage organs including the lungs, heart and brain.

Some people with Hunter syndrome now receive infusions of the IDS enzyme to replace the damaged version. But the healthy enzyme is rapidly depleted, and patients must return every week for a fresh dose.

Mixed results

The Sangamo team looked for ways to permanently replace the enzyme. The company designed gene-editing enzymes called zinc finger nucleases to insert a healthy version of the gene into a region of the genome deemed to be safe. The researchers then used a virus to shuttle DNA that encodes the nuclease, and the healthy IDS gene into liver cells, where IDS is normally produced.

This is an improvement over conventional gene-therapy methods, which do not allow researchers to control where the healthy gene is inserted. That uncertainty has raised concerns that the insertion itself could damage an important gene.

Two of the people in the Sangamo trial showed a decrease in urine levels of the sugars that IDS breaks down. The other two, who received a lower dose, saw no change. No patient report any serious adverse events linked to the therapy.

But researchers failed to detect a concurrent increase in the amount of IDS enzyme in the blood. Sangamo president Sandy Macrae says the company is working on a more sensitive assay capable of detecting low levels of the enzyme, and speculated that the enzyme might be rapidly taken up from the blood by IDS-starved tissues. A clearer answer might emerge as the company tests higher doses of the treatment, he added.

That explanation might not have been enough to placate investors: Sangamo’s stock dropped by 22% in the hours after the presentation.

The data are also difficult to interpret because patients in the trial continued to receive IDS-replacement therapy. A safety panel will evaluate the data later this year to determine whether the trial participants can be weaned off of the treatment, allowing researchers a clearer glimpse into the effects of Sangamo’s editing strategy.

An edited future

Gene editing is a topic of intense interest, due in large part to the development of a powerful technique called CRISPR–Cas9. But although CRISPR–Cas9 is easier to design and use in the laboratory, researchers have more experience using zinc finger nucleases to tinker with genomes.

Previous studies have used zinc finger nucleases to alter the genomes of cells that had been removed from the body. Those treated cells were then infused back into the donor, but Sangamo’s latest trial is the first to perform the editing directly in the body.

Sangamo’s approach differs from what some would define as 'true' gene editing — the use of enzymes to rewrite a mutation and correct it to the healthy DNA sequence — instead introducing an entirely new copy of the gene.

Nevertheless, the Sangamo trial is an important advance for the field, says Marianne Rots, a geneticist at University Medical Center Groningen in the Netherlands. “Obviously, the true gene-editing excitement is in the actual correction of the mutated gene, but this gene-addition study is an important step forward,” she says. “Its outcomes definitely are of interest to a broad range of diseases.”