Twins treated for genetic disorder in the womb
Posted May 14, 2018 12:58 p.m. EDT
(CNN) — Corinna already had one child with a genetic disorder that left him unable to sweat or grow teeth normally.
The disorder -- X-linked hypohidrotic ectodermal dysplasia -- primarily affects boys and can result in overheating, which can be life-threatening in severe cases. It can also affect saliva and tear production.
Corinna and her husband, Tobias, who requested that CNN not use their last name for privacy reasons, discovered the genetic defect when their son was 2 years old and still had no teeth.
"The hotter it is, the more water he needs to cool down his body temperature," Corinna, 40, who lives in Germany, wrote in an email. It's like "the engine of a car that runs without cooling water."
Then, Corinna and Tobias found out that she was pregnant again -- with twin boys. Doctors confirmed that the twins carried the affected gene.
"To be honest, that was what I had almost expected," she said.
By then, Corinna had been in touch with Dr. Holm Schneider, a professor of pediatrics at University Hospital Erlangen who had treated mice and dogs with a version of the disorder by injecting a protein into the amniotic fluid. But this had never been done in humans.
"We were fully aware of the fact that our twins would be the first babies in the world to receive this treatment in utero," Corinna said.
Her twins' cases were published, along with that of a third baby boy, in April in the New England Journal of Medicine.
A medical first
"We realized early that this therapy had worked," Corinna said of the sweat tests that doctors conducted after her twins, Linus and Maarten, were born.
"But only when we discovered wet baby car seats in the first summer, we became really excited about the effect of the treatment," she said.
"They can run as they like to do and can enjoy the sun ... as everybody else without overheating," Schneider, head of Germany's Center for Ectodermal Dysplasias, wrote in an email.
The disorder results from the lack of a functional protein called ectodysplasin A, which signals the development of certain tissues in utero. The treatment the doctors used was a "fusion protein," or "protein-replacement therapy," that contained a key part of the functional protein, the authors wrote. Previous efforts to treat babies with the same protein shortly after birth had failed, Schneider said.
"The drug must be administered at the right time point during development," he said.
Within the first few weeks of pregnancy, an embryo splits into three layers. The outermost layer, the ectoderm, contributes to a number of structures including the skin, teeth, hair and sweat glands. In humans, sweat glands develop between 20 and 30 weeks, the researchers wrote. If they don't form correctly, there may be no going back.
The twins received their first dose at 26 weeks gestation and a second dose at 31 weeks. An unrelated third boy received a single dose at 26 weeks gestation and saw more modest gains in sweating than the twins.
There are a number of genetic disorders that can affect the ectoderm; this approach will not work across the board, experts say. But Schneider believes that "the same approach could be applicable ... for certain genetic orofacial clefts which are not that rare."
"To me, this is the type of paper that we'll probably begin to see more and more of," said Dr. Ignatia Van den Veyver, president of the International Society for Prenatal Diagnosis. Van den Veyver, a professor at the Baylor College of Medicine, was not involved in this research.
It is exceedingly uncommon to treat a fetus with a medication for a genetic disorder, experts say. None of the experts CNN spoke to could identify another prenatal medical treatment for the underlying cause of a genetic disorder.
"I can't think of anything else where we have done that medically," Van den Veyver said.
Unlike their older brother, the twins were able to sweat about the same amount as a normal baby. Now 2 years old, the twins haven't overheated, create normal amounts of saliva and have more tooth precursors than their older brother.
It's too early to say whether the effects of the drug will be permanent in the three boys, the researchers wrote. But Schneider said that "there is no reason to assume that the effects of our treatment wouldn't be permanent" as it was in animals.
"It's really a beautiful story ... but obviously you're going to need a larger trial," said Dr. Ophir Klein, a professor of orofacial sciences, pediatrics and genetics at the University of California, San Francisco.
Klein, whose own research on the same drug is now "on hiatus" due in part to funding constraints, said that there's still research to be done on its safety, how much to give and when. It could also be that the gene in question has other roles later in life, which might not be corrected solely with injections into the womb, he added.
Schneider said that he is "not aware of any relevant risk of the drug" and that his team has "not observed side effects in thousands of treated animals."
"There may be subtle differences (between animals and humans) that we don't know about," Klein said.
There are, however, known risks to inserting a needle inside the womb, including fetal loss and preterm birth, according to Dr. Susan Klugman, board director of clinical genetics for the American College of Medical Genetics and Genomics.
"The risk that we quote to patients is about a 1-in-500 loss rate," said Klugman, also a professor of obstetrics and gynecology at Montefiore Medical Center. "That is clearly a much, much smaller risk than (inheriting) any genetic disorder."
Corinna's twins were born prematurely at 33 weeks. Having twins is also a known risk factor for preterm birth, and the German researchers said they were unable to determine whether the treatment had anything to do with it. The third boy who received the treatment was born full-term at 39 weeks.
Doctors' ability to treat genetic disorders in the womb is limited by how and when a fetus is screened, Klugman said. Genetic disorders in particular are not often tested for in prenatal screens, she added, but some families might test for a specific disorder if they know it runs in the family. Even then, it can take time to get results back, leaving little time to act.
"These tests take time to result. The timing is crucial," Klugman said. "What often happens is: A child is born, a diagnosis is made, and then a couple is worried about that diagnosis for their subsequent pregnancies."
'A very exciting time'
The research was funded in part by Edimer Pharmaceuticals, whose board member and former CEO Neil Kirby assisted in the early experiments. Schneider has also received grant funding from the company, in addition to several research and patient organizations.
Kirby said that "we really have no estimate" of what the cost of the injection would be. The company itself is in flux while it looks for a larger group to take on the project, he said.
Schneider said that he is hoping to conduct a subsequent study of 15 to 20 pregnancies and that he is encouraged by these results.
The twins may not look very different from their older brother -- they have sparse hair and a saddle nose -- but Schneider says there is a big difference across "all features that make up a serious disease." For example, if the twins develop a handful more teeth than their older brother, that could lead to a more developed jawbone.
"Future placement of tooth implants if needed will be much easier," he said.
"It's a very exciting time," Klugman said. "This is exactly where we would like prenatal diagnosis to go -- to be able to act on it."