In a medical first, drugs have reversed an inherited disorder in the womb

April 28, 2018  Source: TechnologyReview 96

The injection of a protein at just the right moment during pregnancy appears to have spared a set of twins—and one other child—from being born without sweat glands.

The daring pregnancy intervention is being described as the first time a drug has been used to treat a developmental disorder in utero.

The experiment, described in a case report today in the New England Journal of Medicine, took place in Germany in 2016 at a clinic that specializes in rare, inherited skin diseases—particular one called XLHED, in which patients are born with fang-like front teeth and without the ability to sweat.

The problem: their bodies don’t produce a specific protein required to make sweat glands.

The German clinic, at the University of Erlangen-Nürnberg, had already participated in a clinical study testing a protein replacement treatment in young children.

But the drug did nothing for the children, the study was abandoned, and the drugmaker, Edimer Pharmaceuticals, shut down.

Enter Corinna T., a German nurse who asked that her name be withheld for privacy. She had already had one son with the disease, which she learned of when he was two.

“He was crying incessantly because he had become too hot,” she recalls. Affected children later learn how to take care of themselves, by lying on cool tile floors or dousing themselves with water.

“It can be life-threatening when they are young. They got hot very fast if you leave them in a car,” says Holm Schneider, the physician who counseled Corinna. “But when they are bigger, they instinctively know to cool off.”

Corinna says she then became pregnant with twins, and at 21 weeks into her pregnancy, an ultrasound revealed that they had the same disorder.

Even though Edimer’s drug had failed to help kids, it had worked when injected into pregnant animals. Corinna and her husband asked Schneider: would in utero treatment be possible for the twins?

“We were hesitant,” he says. “In that situation you think twice. You think more about the risks involved—three lives—but also the chances that it may bring.”

Within a month, Schneider had agreed to attempt a cure, and so had his university, under a “compassionate use” exemption. He was able to obtain doses of the drug left over from Edimer’s trial.

The treatment exploited the fact that the missing protein is needed only temporarily, between weeks 20 and 30, when the sweat glands form in a developing fetus. Schneider says his team injected it directly into the twins’ amniotic sacs.

“The great thing about this is the critical time points in the intrauterine development of these sweat glands,” says Anna David, director of the Institute for Women’s Health at University College London. “I think it is the first time you are seeing a protein drug used for correction of a genetic disorder before birth.”

Other diseases, like hemophilia, couldn’t be treated this way, because the body requires constant supplies of the missing molecules. Eventually, scientists may consider fetal gene therapy, which would add an entire new gene to a baby’s cells, although David says that has never been tried.

Corinna, the nurse, says she thinks the XLHED treatments worked. “Extremely successful,” she says. “The twins can sweat normally.” They still have somewhat unusual facial features and missing teeth.

Other parents now want the treatment too, and Schneider says he hopes he can organize a clinical trial with the help of a charitable foundation. The team treated the fetus of one other woman after its success with Corinna, but it has not tried again.

It’s unlikely any company would want to market the drug for treating fetuses, even if it works. The disease is too rare—perhaps affecting 1 in 25,000 people—and treating babies in the womb is something few companies would attempt, because it can pose risks to the pregnant woman.

“If you wanted to make this for the patient community, and administer it once in life, the chance that it will ever be profitable is very low,” says Schneider. “Yet here you have an incurable disorder, no drug available, and here is something working—three out of three.”

By Ddu