Successful treatment of a rare genetic disorder in the womb

For the first time, an inherited disorder has been reversed in babies before birth.

“There are a number of conditions for which we would seek treatment in utero, but traditionally these have been non-genetic, non-inherited conditions,” Dr. Maisa Feghali, an assistant professor of maternal fetal medicine at the University of Pittsburgh, who was not involved in this study, told STAT.

The disease, X-linked hypohidrotic ectodermal dysplasia (XLHED), affects about 1 in 17,000 people worldwide. Patients with XLHED carry a mutant gene that prevents the production of a certain protein, called ectodysplasin A. Lacking this protein causes abnormal development of structures such as the skin, nails, teeth, and sweat glands. The reduced ability to sweat (called hypohidrosis) can lead to dangerous overheating, causing potentially life-threatening health problems.

In a previous clinical trial, babies with XLHED were given ectodysplasin A within weeks of birth. Unfortunately, the clinical trial was ended in 2016, and deemed unsuccessful after seeing no significant improvement in the children.

However, a new study took advantage of the “sweet spot” in prenatal development when the sweat glands form, between 20-30 weeks of pregnancy. The three babies treated in this study, a set of twins and another single baby, all had siblings with XLHED, and were diagnosed with XLHED by 22 weeks of pregnancy.

In 2016, the scientists directly injected the protein drug left over from the previously unsuccessful clinical trial into the amniotic sacs of the twins at 26 and 31 weeks and the single baby only at 26 weeks. Soon after birth, the twins showed a normal number of sweat glands, and the single baby showed only slightly fewer sweat glands than normal.

Now, 14-22 months after birth, the babies can sweat normally and haven’t developed any XLHED-related illnesses; however, they still have somewhat unusual facial features and some missing teeth, which are commonly seen in XLHED patients.

“[T]he remarkable part here [is] that a genetic disease can be at least partially corrected by a short-term protein treatment,” Marja Mikkola, a developmental biologist at the University of Helsinki, who wasn’t involved in this study, told STAT.

“Some disease treatments involve providing something that is faulty or missing (e.g. insulin for diabetics), but to actually alter how the body builds itself in the womb is amazing,” added Katherine W. Rogers, a developmental biology postdoc at the Friedrich Miescher Laboratory of the Max Planck Society.

This treatment can be compared to ‘teaching someone to fish’ rather than ‘giving someone a fish’, like some other treatments require.

While the treatment isn’t fully curative, the most life-threatening aspect of the disease was successfully addressed. Long-term follow-ups are needed to ensure that the positive effects last throughout the patients’ lifetimes and that there are no long-term side effects for the mothers.

Acknowledgements: Thank you to Katherine W. Rogers for her commentary on this study and its implications.

Managing Correspondent: Chelsea Weidman

Press Articles: Doctors Successfully Treat Rare Genetic Disorder in Utero. The Scientist.

In a medical first, drugs have reversed an inherited disorder in the womb. MIT Technology Review.

‘A full rescue’: Drug injected before birth treats rare genetic disorder. STAT.

Original Journal Article: Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia. The New England Journal of Medicine.

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