On Monday, November 13, Brian Madeux became the first patient to receive an experimental therapy designed to alter his DNA. The 44-year-old has a rare metabolic disease called Hunter syndrome, a disorder caused by missing or malfunctioning enzymes that result in a buildup of certain substances in the body, producing permanent and progressive damage to everything from organ function to mental development. At UCSF Benioff Children’s Hospital in Oakland, Madeux received hope in the form of a simple IV that dripped billions of copies of a corrective gene, along with a genetic snipping tool that zipped to the exact right location in his liver.
The snipping tool — a set of enzymes called zinc finger nucleases (ZFNs)— is part of a gene- editing treatment developed by Sangamo Therapeutics. It functions similarly to the newer kid on the block, CRISPR, in that it seeks and cuts a specific piece of DNA. Once a double-stranded break is created, a new gene can slip in, enabling the production of a stable supply of proteins that the patient lacked.
While scientists have used CRISPR and other gene-editing techniques, including ZFNs, to change people’s DNA in the past, they’ve had to harvest cells first, modify them in a lab, and then transfuse them back into the body.
“The remarkable thing about this trial is that vectors encoding the zinc finger nucleases and the donor DNA molecule were introduced into the body, and everything is taking place in the body,” says R. Scott McIvor, a genetics researcher at the University of Minnesota’s Center for Genome Engineering, who conducted some of the preclinical work for the Sangamo trial. If Madeux’s treatment is successful, it could pave the way for in vivo [inside the body] gene editing for a wide range of genetic disorders, he says.
Past gene therapies that have attempted to deliver DNA to patient cells without these gene-editing tools have been largely unsuccessful. Sometimes the viruses used to deliver the corrective genes provoked severe immune system reactions in patients. In other cases, the new gene was inserted at random in the recipient’s DNA, inadvertently disrupting neighboring genes and leading to other health problems.
“There’s still going to be a concern when trying to permanently alter someone’s genes,” says Brendan Lanpher, a clinical geneticist at the Mayo Clinic in Rochester, Minnesota, who was not involved in the Sangamo trial. But with zinc fingers, scientists and clinicians will be able to be more precise and, hopefully, minimize unwanted effects, he says.
One advantage of ZFNs is that they can be customized to recognize virtually any three-letter groove in the entire genome. By stringing multiple ZFNs together, researchers can quickly engineer them to be highly specific. And Sangamo has been working to improve the technology since the late 1990s. Tests in various animal models have proven it is safe and effective, McIvor says. So now ZFNs will be able to recognize and swap out DNA in people too.
In patients with Hunter syndrome, Sangamo’s ZFN therapy will adjust for a mutation in the IDS gene that results in a reduction or complete elimination of a carbohydrate-recycling enzyme. Without the enzyme, carbohydrates accumulate and cause problems that range from bunions and hernias to distorted bones, excessive bowel movements, and progressive cognitive deterioration. “It really affects essentially every system. It’s a pretty nasty disease,” Lanpher says.
Indeed, Madeux has already undergone 26 operations to fix problems caused by his disease. Although gene therapy won’t reverse the damage that his body has already sustained, it may be a long-lasting alternative to the weekly infusions of enzyme replacement therapy he needs. The current standard-of-care treatment costs between $100,000 to $400,000 a year.
In about a month, scientists will know if the treatment is working as hoped. Tests will show for sure in three months. Even then, researchers will need to monitor whether the clinical effects of the experimental therapy are significant, Lanpher says. “It’s one thing to put the gene in, but does it actually make a difference for the patient is going to be an important question to answer.”
Ultimately, the goal is to treat children early, before too much damage occurs. And because Hunter syndrome occurs in approximately 1 in 100,000 to 1 in 170,000 males, Sangamo’s in vivo ZFN therapy has received Fast Track and Orphan Drug designations from the Food and Drug Administration. The company has two additional clinical trials underway to test similar therapies for hemophilia B, a hereditary bleeding disorder, and Hurler syndrome, another rare metabolic disease. “In vivo gene editing is going to be the way going forward,” McIvor says.