A bold attempt this month to cure a lethal genetic disease by editing DNA inside a patient was carried out in San Francisco and made headlines around the country — but it was based largely on mouse research at the University of Minnesota Medical Center.
Now, the second, third and additional attempts may occur in Minneapolis — as researchers race to prove the safety and effectiveness of editing genes inside patients.
“Things are moving forward so fast,” said Scott McIvor, a U specialist in genetic diseases and gene therapy. “I never would have dreamed you can do what you can do right now.”
McIvor and Dr. Chester Whitley used mice to test an approach developed by Sangamo Therapeutics to splice DNA strands in a precise chromosomal spot to correct genetic deficiencies.
The corrections in this case sought to address enzyme deficiencies that are disabling and often fatal in patients with two genetic diseases, Hunter syndrome and Hurler syndrome. Diseased mice that received the gene therapy did better at maze experiments, suggesting that it could provide a safe and therapeutic benefit in humans.
The animal tests ultimately led researchers at the University of California-San Francisco to try the experimental therapy on a 44-year-old with Hunter syndrome.
Gene editing has been attempted before by targeting cells outside the body (ex vivo) and transplanting them back into patients, but never before directly in the body (in vivo).
Four hospitals are pursuing additional patients. Whitley said three patients at the U are already under consideration.
“They’re trying to decide if it’s an appropriate risk vs. benefit to become one of the next gene-edited human beings,” Whitley said.
The U is a global expert on Hurler, which when left untreated causes children to develop physical deformities and mental retardation, and usually results in death by age 10. The U has performed one fourth of the bone marrow transplants worldwide to boost enzyme levels in these patients, prevent disabilities and prolong their lives.
Transplants have limits. If patients’ immune systems reject the donor bone marrow, the transplants can result in complications or death. And they don’t produce enough of the missing enzyme to address all the deficiencies in Hurler patients, McIvor said.
A key challenge has been creating a “vector,’’ often a mutated virus, that directs genetic therapies at precise locations in the DNA and coaxes them into action. Sangamo’s approach uses three adeno-associated viruses that target cells in the liver, which seem to be particularly good at reproducing genetic corrections and spreading them throughout the body.
Whitley used white blood cells two decades ago to target a gene therapy in Hunters patients. The ex vivo attempt was a crude “shotgun” approach to gene editing, he said, compared to the “GPS-like” precision that exists with today’s methods.
Whitley and McIvor have financial consulting relationships with Sangamo, as well as their own experimental approaches. Whitley said Sangamo’s approach appears the closest to producing an approved therapy, and prompted him to drop work on an approach he had patented.