In November, scientists made history when they conducted the first-ever gene-editing therapy inside the body of a living human — an achievement made possible in part through preclinical data collected at the University of Minnesota.
R. Scott McIvor, a professor in the Department of Genetics, Cell Biology and Development and the Center for Genome Engineering, and Kanut Laoharawee, a master’s degree student in McIvor’s lab, set out in summer 2014 to discover whether a therapy developed by biotechnology company Sangamo Therapeutics could effectively treat mice with Hunter syndrome (also called MPS II). The successful results, completed in 2016 and published last month in Molecular Therapy, played a pivotal role helping Sangamo reach FDA approval to begin clinical trials.
The Hunter syndrome study was one of two sponsored research projects Sangamo brought to the University of Minnesota. The other, led by Chester Whitley, professor of pediatrics in the University’s Medical School, focused on preclinical data for the related Hurler syndrome (MPS I). What these diseases have in common is the body’s genetic inability to produce certain enzymes it needs to function correctly.
In Hunter syndrome, that means a lack of the enzyme that breaks down glycosaminoglycans (GAGs). Left unchecked, GAGs build up in cells across the body and wreak havoc, causing joint deformities, respiratory issues, neurological problems, and more. Patients can get enzyme injections, but the treatments are expensive and require frequent appointments.
Instead of injecting enzymes, Sangamo’s therapy is designed to teach the body to make its own. Using zinc finger nucleases (a gene-editing tool that predated TALEN and CRISPR), the therapy “patches” a genetic sequence into liver cells that reprograms them to mass-produce the missing enzyme, allowing the body to break down GAGs. McIvor saw potential in the approach.
“Sangamo came to us with a proposal to do something different,” he recalled. “I looked at it and thought, ‘this is going to work.’”
In the lab, Laoharawee tested different dosages of Sangamo’s therapy on young mice with Hunter syndrome, hoping to see them produce enough of the missing enzyme to prevent their GAG levels from building up. He found levels of the missing enzyme skyrocketed in treated mice to 200 times that of regular mice, and their GAG levels were 95 percent lower.
Surprisingly, Laoharawee also found mice who received the highest dosage didn’t suffer the neurocognitive issues common in severe Hunter syndrome, meaning the enzymes had somehow benefited the brain — a difficult feat given that the body’s blood-brain barrier (a filter for keeping out potentially harmful or unrecognized substances) often vexes scientists by blocking therapies from reaching the brain.
“We were very excited about the result,” said Laoharawee, who continues his genetic engineering focus as a Ph.D. student in CBS’s Molecular, Cellular, Developmental Biology and Genetics Program. “As expected, the enzyme activity increased drastically with the treated group.”
Going forward, Sangamo’s clinical trials will reveal whether the therapy will show similar success in humans. The multisite clinical trials for Hunter syndrome and Hurler syndrome, which include an effort led by Dr. Whitley to recruit and treat patients at the U of M, have already treated two participants in Oakland, CA, with Hunter syndrome, and there are more to follow.
“These are the only two patients in the world that have been treated through in vivo gene editing,” McIvor said. “The genetic modification is taking place in the tissues of the body—that’s the remarkable thing about it.” –Kevin Coss