In first, doctors treat rare genetic disorder with an injection in utero

Three babies with a rare genetic disorder have been spared the worst effects of their condition thanks to an experimental injection they received in utero, researchers report this week in  .

The success marks the first time a genetic disorder has been partially reversed by such a treatment prior to birth. The results are “remarkable and encouraging,” development biologist Marja Mikkola at the University of Helsinki, Finland wrote in an accompanying editorial.

“This study paves the way for a larger trial of this novel approach.”

The in utero injections treated a rare, recessive genetic condition called X-linked hypohidrotic ectodermal dysplasia (XLHED), which affects the development of skin, hair, nails, and teeth. People with the disorder have sparse body and head hair, dry eyes, mouths, and airways, and few teeth, which are usually pointy. But most dangerously, the condition also disrupts development of sweat glands throughout the body. People with XLHED have fewer sweat glands and/or poorly functioning ones. This leaves individuals vulnerable to high fevers and over-heating (hyperthermia), which can be life-threatening and lead to medical complications.

The most common cause of XLHED is a mutation that breaks the functioning of a gene called (ectodysplasin A), which encodes a signaling molecule in the body. In early embryos, this molecule is critical for coordinating the activity of cell layers, from which organs and tissues develop.

Fifteen years ago, researchers figured out that they could essentially fix the genetic condition in animals by dosing them early in life with a lab-made protein that mimics the role of the missing signaling molecule. The gene is highly conserved in vertebrates, so it’s easy to replicate (and cure) the disorder in animals, which has been done in mice and dogs. But in an early clinical trial, when researchers gave the treatment to human babies in the first few weeks of life, it didn’t work.

Timed delivery

For the new experimental treatment, the researchers realized that it all came down to timing. Humans develop sweat glands much earlier in their development, generally between the 20th and 30th week of pregnancy. To prevent XLHED from wreaking havoc, the researchers needed to deliver the protein prior to birth.

After testing the idea for safety and efficacy in mice and monkeys, doctors in Germany got a compassionate-use approval to try it in a 38-year-old pregnant woman. She had a family history of XLHED, a young son with the condition, and was found to be carrying twin boys with it, too.

At 26 weeks of gestation, the researchers removed amniotic fluid from each of the twin’s amniotic cavities and injected a high dose of the lab-made protein (100mg per kilogram of estimated fetal body weight). They repeated the treatment at week 31 of gestation. The idea was that the fetuses would take in fluid containing the protein, which would then spread systemically through its growing body and restore normal development.

Two weeks after the second treatment, the twins were born prematurely by cesarean section, both weighing less than four pounds. Despite their early start, they were generally healthy. Moreover, they seemed to have a normal amount of sweat glands in their feet and produced normal amounts of sweat compared to control infants. In their first 22 months of life, they had no hyperthermic episodes and produced normal amounts of baby slobber. They also had the makings of eight and ten teeth, respectively, compared to their five-year-old brother with the condition, who had four.

The researchers repeated the treatment in another pregnant woman who was carrying a single baby with the condition. Because of a shortage of the protein, the doctors were only able to deliver one injection at 26 weeks. The woman gave birth at 39 weeks to a 7.6 pound baby. He had fewer sweat glands and produced less sweat than the twins but more so than untreated babies with the condition.

The researchers will track the babies’ development to see if the effects are permanent, but data from animals suggests that they will be.

, 2018. DOI:10.1056/NEJMoa1714322 (About DOIs).

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