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Brian Madeux, who has Hunter syndrome, did not appear to benefit from the low dose of a gene-editing treatment that he received.

Eric Risberg/AP Photo

New gene-editing treatment might help treat a rare disorder, hints first human test

The first test of a new gene-editing tool in people has yielded early clues that the strategy—an infusion that turns the liver into an enzyme factory—could help treat a rare, inherited metabolic disorder. Today, the biotech company Sangamo Therapeutics in Richmond, California, reported data suggesting that two patients with Hunter syndrome are now making small amounts of a crucial enzyme that their bodies previously could not produce. But the company is still a long way from providing evidence that the new method can improve Hunter patients’ health.

Hunter syndrome results from a mutation in a gene for an enzyme that cells need to break down certain sugars. When these sugars, called glycosaminoglycans (GAGs), build up in tissues, they damage organs such as the heart and lungs, sometimes leading to developmental delays, brain damage, and early death.

The new treatment uses a gene-editing tool called zinc finger nucleases (ZFNs). ZFNs were developed earlier than CRISPR, the hugely popular gene-editing tool, and Sangamo has already used them to edit cells in a dish that were then returned to a patient’s body.

Sangamo’s new results are for four men with a mild form of Hunter disease. The participants were already receiving a standard Hunter syndrome therapy: weekly injections of iduronate-2-sulfatase (IDS), the enzyme they lack. However, blood levels drop within a day of injections, limiting their effectiveness.

To test the ZFNs, Sangamo injected patients with harmless viruses that ferry DNA for the nucleases into their liver cells, along with a good copy of the IDS gene. The ZFNs snip DNA in a specific location, which the cells then repair using the provided IDS gene. The landing spot is within the gene for the protein albumin, which has a strong on–off switch that controls the new IDS gene. Because of this powerful promotor, less than 1% of a person’s liver cells may produce sufficient amounts of IDS to treat Hunter disorder, says Sangamo President and CEO Sandy Macrae.

Last November, Sangamo treated the first patient in its trial, Brian Madeux. Today, geneticist Joseph Muenzer of the University of North Carolina in Chapel Hill, principal investigator for the trial, reported results for Madeux and three more patients at a meeting in Athens, Greece.

Muenzer’s team tested patients’ urine for GAG on the day before they received their weekly IDS injection—the point when GAG levels are their highest. After 4 months, the two men who received the lowest of three planned doses, including Madeux, weren’t producing any less of the toxic sugars. But the two who got the medium dose saw their GAG levels drop substantially compared to the past levels—by 39% and 63% respectively.

But their bodies weren’t making detectable blood levels of IDS, the company reported. Sangamo says the standard assay for IDS may not be sensitive enough to pick up on low levels that are nevertheless beneficial. Others are cautious. "It's hard to know what's really going on,” said gene therapy researcher Mark Kay at Stanford University in Palo Alto, California, after seeing Muenzer’s slides. The decrease in GAGs suggests some IDS expression, but the lack of the enzyme in the blood goes against that result. “I think it’s going to take more time before we know how well this works.”

The treatment seemed safe. Only one patient on the middle dose had elevated liver enzymes—indicating an immune response—which soon went down. (The safety data included one patient who received the highest dose.)

Later, middle-dose patients will go off enzyme replacement therapy, and researchers will see if their GAG levels stay low. They will also see whether patients’ scores remain stable on tests of walking ability and lung function, which gradually decline in those with untreated Hunter syndrome. To see if the ZFNs are working, researchers will also need to analyze biopsied liver cells to confirm that the IDS genes are being inserted as planned—not in unintended locations that could potentially trigger a cancer gene.

The company says the therapy should work better in two patients who recently received the highest of the three doses. But even if the ZFN-treated cells produce therapeutic levels of IDS, a question looms over the company’s plans to one day treat boys with more severe Hunter disease. High GAG levels in these patients can lead to brain damage that can’t be prevented with enzyme replacement because IDS doesn’t cross the blood-brain barrier.

A Sangamo-sponsored mouse study suggests that the ZFN-produced IDS does get into the mouse brain. But people have a less permeable blood brain barrier. “I am excited about this approach,” says gene therapy expert Beverly Davidson of the University of Pennsylvania Perelman School of Medicine. But, “There’s not enough data to suggest that the protein will reach the brain.”