s soon as she saw her baby, Sarah Yaroch knew. Her father had the disorder, as did her nephew, and now she could see the telltale signs in her own newborn son Andrew. He had no eyebrows, no hair, and skin that seemed too pale and thin. A genetic mutation had deprived him of a specific protein as he developed in the womb, and without it, his body could not properly form sweat glands and teeth and other organs.
Within two weeks, though, he was brought from Waterford, Mich., to St. Louis, where doctors infused an experimental lab-grown version of the protein into his tiny veins. The hope was that giving this molecule just after birth might compensate for what had been missing during pregnancy.
But two years later, in 2016, the clinical trial was stopped — the treatment hadn’t worked. The study coordinator phoned Yaroch with the news. “I said, ‘OK, thank you,’ and she said, ‘Do you have any questions?’ and I said no, and we hung up,” Yaroch recalled. “I think I was just shocked that it was canceled like that.”
Now — after two companies that had been trying to make the molecule have gone out of business, and families like Yaroch’s were disappointed to see little improvement when it was given to their newborns — researchers in Europe say they have gotten it to work. Their trick was simple: inject it into the amniotic fluid during pregnancy.
They published promising results from three kids on Wednesday in the New England Journal of Medicine, not only restoring hope for those that carry this particular mutation, but also opening up the possibility of treating genetic disorders with drugs in utero.
“It’s quite a remarkable advance … to be able to really alter the outcomes significantly for these affected fetuses,” said Dr. Maisa Feghali, an assistant professor of maternal fetal medicine at the University of Pittsburgh, who was not involved in the study. “There are a number of conditions for which we would seek treatment in utero, but traditionally these have been non-genetic, non-inherited conditions.”
A success in animals, failure in newborns
The disorder in question is called X-linked hypohidrotic ectodermal dysplasia — or XLHED, for short — and is quite rare, affecting an estimated 1 in 17,000 people worldwide. The most serious consequence is that these patients have no sweat pores, and so can get dangerously overheated.
The kind of genetic mutation that causes it naturally occurs in other mammals, too, and that was where this drug came from in the first place.
In 2008, Dr. Philip Reilly, a geneticist-turned-investor at Third Rock Ventures in Boston came across a paper he found striking. It was about a protein that, when given to newborn dogs, could correct some of the issues caused by this genetic mutation. “I saw the pictures of the dog, I saw its X-ray, and I said, ‘This dog has the same disease as people,’” Reilly said.
That was the germ for what would become Edimer Pharmaceuticals. Researchers in Europe had already collaborated with two different companies: One that didn’t survive, and one that had let the compound languish on a shelf. Now, with money from the American biotech bubble, Edimer and the European researchers were going to try to get it into patients.
When the protein was injected into the bloodstream and the amniotic fluid of pregnant mice, it corrected the genetic anomaly. But repeating the same experiment right away in humans was out of the question.
The research team knew that they needed to give the drug as early as possible, but they also knew that regulators and ethics committees weren’t going to like the idea of first-in-human studies on fetuses or even newborns, so they started by showing that it was safe in adults who had that genetic mutation, even though the drug wouldn’t help them personally.
Then came the hard part. Mice and dogs with this kind of genetic mutation might have similar symptoms to humans with XLHED — but their development in the womb is very different from ours.
“I really didn’t like the idea of dosing the mother to get the drug into the fetus, because you’re actually dosing two people, and there is no real need for that,” said Neil Kirby, who was the CEO of Edimer and who is an author on the new paper.
So, with the help of patient groups like the National Foundation for Ectodermal Dysplasias, they started seeking pregnant women who had this mutation, to see if they might be willing to have their babies treated almost immediately after birth.
“It raised some hope, because in animal models we had seen that some effects could also be achieved post-natally, but we were not full of hope,” said Dr. Holm Schneider, the first author of the new paper, who is a professor of pediatrics at the University Hospital Erlangen and head of the Center for Ectodermal Dysplasias, both in Germany. “We knew we would come too late for several aspects for ectodermal development.”
Proof in a sweaty car seat
The call came in December of 2015. It was a woman from the heart of Lower Saxony named Corinna T. She had a son with XLHED, and she was 14 weeks pregnant. It was too early to know for sure, but she thought she might be carrying twin boys, and was worried they’d also be affected. Could Schneider help?
The results from the newborn trial were not looking good at that point. Even with the drug, the participating babies weren’t able to sweat.
Schneider told the family that all he could promise at that point was a diagnostic ultrasound: By week 22, you can see the beginnings of teeth in the fetal jaws, and so can tell whether or not the baby has XLHED. When Corinna came in, it was clear that her babies did.
“We told the couple … that there is probably no chance to get any treatment for the affected twins, other than something that has not happened before in the world,” Schneider recalled. He sent them back to Lower Saxony to think.
A few weeks later, a decision was made: They would inject some of the drug left over from the infant experiment into Corinna’s pregnant belly.
As Corinna explained in an email to STAT, “It gave us the opportunity to facilitate the lives of our twins, because being unable to sweat can be life-threatening. We knew: If it doesn’t work we will accept the twins as they are.”
In late February, in the 26th week of the pregnancy, the doctors sucked out a little bit of her amniotic fluid, and injected some of the drug. They did it again a few weeks later, and then a few weeks after that, Linus and Maarten were born prematurely, by caesarean section.
There were more urgent issues to take care of than testing sweat levels, but it was soon obvious that moisture formed on their foreheads and noses. When examined under a microscope, the soles of their feet had a normal number of sweat glands, unlike their older brother Joshua.
But these tests can be performed only on certain parts of the body. It was only that summer, when the parents saw that one of their twin boys had soaked a car seat with his sweat, that they got really excited about how well the treatment had worked. They snapped a picture and sent it to Schneider. “A full rescue of sweating ability — that was so great, just unbelievable,” Corinna said.
Another family, also with one son affected by XLHED, had heard about this experiment, and asked Schneider about getting the same treatment. He agreed, though he had just enough drug left in the freezer for a single dose. After that baby was born, he had slightly fewer sweat pores than he should have — but he had nine teeth germs, while his 2-year-old older brother had only two.
While all that treatment and testing was going on, Edimer’s experiment in newborns was deemed a failure, and the company’s investors decided the drug wasn’t worth pursuing.
“It’s disappointing for everybody, it’s disappointing for the patient community, it’s disappointing for the investors,” said Kirby, who was the CEO. “It’s a reminder that not everything translates from animals to humans.”
But Kirby is thrilled with the success among the first three patients to get the drug before they were born.
“That’s the remarkable part here, that a genetic disease can be at least partially corrected by a short-term protein treatment,” said Marja Mikkola, a developmental biologist at the University of Helsinki, in Finland, who wrote an accompanying editorial about the article and was not involved in the study.
Now, the researchers are planning a bigger clinical trial with the help of a nonprofit foundation that will take over the drug’s development. As exciting as it is, finding participants for a larger study will involve some strange questions. “This is a very interesting clinical and ethical problem: Who is your patient?” said Reilly, the geneticist-turned-investor. “You need to identify women who are carriers who are not yet pregnant. You’re developing a drug for patients that haven’t been conceived yet. It’s really unusual.”
For the parents who had their babies treated after birth, this study comes as a relief. “I’m not upset that it didn’t work for my child,” said Yaroch. “I’m grateful that people are still working on it, because if it would have stopped with the trial that Drew was in, my grandkids could have it and not have had a cure.”
The drug may not be perfect, but the researchers think its positive effects will last for the rest of patients’ lives. As Schneider put it, “We have to wait another 80 years to be sure it’s true.”