Very first successful attempts at therapy for genetic disorder ectodermal dysplasia

Thanks to prenatal protein injection, the condition is no longer life-threatening for three children

One in 30,000 children suffer from ectodermal dysplasia. During attempts to treat the disorder in utero, a team of doctors led by Prof. Dr. Holm Schneider from the Department of Paediatrics and Adolescent Medicine at Universitätsklinikum Erlangen succeeded in correcting the genetic disorder by injecting a protein into the expectant mother’s amniotic fluid. The results of the successful treatment have been published in the New England Journal of Medicine.

Joshua, the five-year-old son of Corinna and Tobias T. from near Bremen, suffers from the genetic disorder ectodermal dysplasia. Joshua only has three pointed teeth, hardly any hair, pale, dry skin – and he is unable to sweat. If his surroundings are too warm, Joshua automatically lies down on the cold floor. If his body overheats, it could have fatal consequences. Once Joshua’s parents discovered that their son was suffering from the disorder and realised that Corinna T. was a carrier of the genetic defect, they were faced with the dilemma: do we want a second child or not? The risk of having another baby with ectodermal dysplasia was 50:50.

Then Corinna T. became pregnant with twins. The sad news: they would be ill as well. ‘We are sorry, but we can only see two teeth buds developing’, announced the obstetrician after the detailed ultrasound scan. Through a self-help group, the couple were already in touch with the experts for ectodermal dysplasia at Universitätsklinikum Erlangen. In order to give twins Linus and Maarten the chance of a better life, Corinna and Tobias T. decided to go ahead with the attempt to treat the disorder in utero, the very first time it had been attempted anywhere in the world. ‘We didn’t have anything to lose. Someone has to be the first,’ explains Corinna T. The treatment was carried out in February 2016 by Prof. Dr. Holm Schneider, Senior Consultant at the Department of Paediatrics and Adolescent Medicine and spokesperson of the Centre for Ectodermal Dysplasia Erlangen and Senior Consultant PD Dr. Florian Faschingbauer from the Department of Obstetrics and Gynaecology at Universitätsklinikum Erlangen.

In utero protein replacement therapy

Ectodysplasin A1 (EDA1) is a protein normally found in the body. During the development of the child in the mother’s womb, it ensures that hair, teeth and skin appendages such as sweat glands are produced. Foetuses with X-chromosomal hypohidrotic ectodermal dysplasia (XLHED) lack the EDA1 protein – as was the case with twins Linus and Maarten.

As part of the successful attempt at treatment at Universitätsklinikum Erlangen, Prof. Dr. Schneider and PD Dr. Faschingbauer injected a replacement protein into the womb of Corinna T.: first of all into the amniotic sac of each twin in the 26th week of pregnancy, followed by a second injection 39 days later. The doctors from Erlangen treated a third boy a single time – in the 26th week of pregnancy. Using ultrasound to oversee the procedure, PD Dr. Faschingbauer carefully injected 15 ml of the medicine into the amniotic fluid, taking care not to touch the foetus. The unborn children swallowed the protein with the amniotic fluid and absorbed it into their own bloodstream through their intestines. ‘The medicine would not reach the child’s body via the mother’s bloodstream, as it would not pass through the placental barrier, the tissue filter which keeps the mother’s blood separate from the child’s blood,’ explains Prof. Dr. Schneider. ‘The only way for EDA1 to reach the bloodstream of the unborn child was therefore to inject it directly into the amniotic fluid.’ EDA1 alone is not enough, however. What makes the new method of treatment so ingenious is the vehicle used to transport the replacement protein into the bloodstream: the so-called Fc components of human antibodies. Babies’ digestive systems have a special absorption mechanism which ensures that antibodies from the mothers’ milk are transferred into the infants’ bloodstreams. Prof. Dr. Schneider and his colleagues used this mechanism to smuggle in the therapeutic protein.

All three of the children treated in utero formed sweat glands and additional tooth buds as a result of the protein injection. The first boy treated was able to sweat adequately after he was born. The twins Linus and Maarten even sweat like normal children, as proven by the regular measurements carried out by Prof. Dr. Schneider every eight to twelve weeks as well as microscopic images of the sweat glands. ‘The most obvious proof that the treatment was successful has to be the photo of a baby car seat soaked in sweat sent to me by Corinna T. several months after the twins were born. She had never experienced anything like that with her son Joshua,’ says Holm Schneider. ‘Anyone who can sweat, can also run – to their heart’s content,’ and that is exactly what the nearly two year old twins do.

Thanks to the trial, all three treated children now have considerably more teeth than their older siblings with ectodermal dysplasia, who did not have the benefit of the treatment. ‘We have researched the EDA1 protein for years and tested the medicine in clinical trials,’ explains Prof. Dr. Schneider. ‘The last study in which the protein was given to newborns with the disorder demonstrated that we cannot influence the development of sweat glands after a child is born. Our conclusion was: the treatment has to be carried out whilst the child is still in the mother’s womb – otherwise it is too late.’ The success of the therapy shows that the doctors from Erlangen were right. The three children who have been treated now do not have to live with the threat of dying from overheating – a fate suffered all too often by children with XLHED.

The new procedure offers mothers who carry this form of ectodermal dysplasia the opportunity to have children who no longer have the most serious symptoms of the disorder. This means a huge increase in the quality of life for affected families. In addition, protein replacement therapies in utero could possibly also be used in future to treat other foetal developmental disorders, such as cleft lips.

Strict ethical requirements – multicentre clinical trial to follow

The treatment carried out at Universitätsklinikum Erlangen was not part of a clinical trial, it was only an attempt to treat three children. The procedure was subject to strict ethical requirements. ‘We wanted to inject the protein early enough in the pregnancy to be able to influence the development of sweat glands and teeth,’ explains Prof. Dr. Schneider. ‘However, we wanted to delay the injection as long as possible to avoid triggering an extremely premature birth, which could have put the infants’ lives in danger.’ The foetus forms sweat glands some time between the 20th and 30th week of pregnancy. After weighing up all the pros and cons and consulting at length with the Clinical Ethics Committee at Universitätsklinikum Erlangen, the 26th week of pregnancy was determined as the earliest possible date for an injection.

Linus and Maarten were born by caesarian section in the 33rd week of pregnancy, the third boy who was treated prenatally was born in the 39th week. All three children have benefited considerably from the in utero therapy. ‘Working together with other centres in Germany, France and the UK, we would now like to carry out a clinical study on a larger group of unborn children in order to prove the positive effects of the in utero treatment’, announces Prof. Dr. Schneider. The experts from Erlangen are cooperating with the non-profit Swiss foundation EsperRare, that develops medicines for treating rare diseases.

Prof. Dr. Schneider has been looking after and treating children and young people with ectodermal dysplasia for nearly 20 years now. He teaches parents how to prevent their children from suffering from heatstroke, how best to deal with constantly blocked up ears and noses, frequent infections and dry eyes and how the missing teeth can be replaced with dentures or implants. He is well aware: ‘The unusual appearance of those affected is not the main issue. They have to deal with much more serious problems such as the potentially fatal threat of overheating and the considerable restrictions on the quality of life entailed by the inability to regulate temperature properly. According to one of our patients, not being able to sweat is like ‘driving with an engine without a cooling system’.’ After investing decades of research, the prenatal protein replacement therapy has enabled Prof. Schneider and his colleagues to correct a genetic developmental disorder which has until now been untreatable.

Background: ectodermal dysplasia

Ectodermal dysplasia are inherited genetic defects. They cause deformities (dysplasia) in structures stemming from the ectoderm. It affects the outer ectoderm of the embryo, from which skin and its appendages are formed. Deformities affect skin, sweat, sebaceous and scent glands, hair, nails, teeth, mammary glands and eyelids.

There are more than 150 different types of ectodermal dysplasia. X-chromosomal hypohidrotic ectodermal dysplasia (XLHED) accounts for 80 to 90 percent of all cases. The gene EDA, which is found on the X chromosome, is mutated in those suffering from the disorder. As boys only have one X chromosome, they are more severely affected than girls, who have one healthy X chromosome in addition to the defective one. The inheritance pattern for X chromosomes means that if a father (one X chromosome) is affected by XLHED, his sons will always be healthy, but each of his daughters will carry the defect. If the mother (two X chromosomes) has the disorder, her sons and daughters have a 50 percent chance of having the gene defect.

People with XLHED have a distinctive appearance: few, often pointed teeth, low-set, sticking-out ears, missing eyelashes and eyebrows, sparse, lightly pigmented scalp hair, flaky and extremely dry skin, dark rings under their eyes and a flattened bridge of the nose. The lack of sweat glands can be life-threatening for those affected, especially up until the age of two: ‘Young children are not yet able to cool themselves down, for example if they are left in direct sunlight, run around and play outside in the summer or are in a heated room or vehicle. The risk of suffering potentially life-threatening heat stroke is considerable,’ according to Prof. Dr. Schneider. Missing tooth buds in a foetus are a clear indication of ectodermal dysplasia. Tooth buds can be counted whilst the foetus is still in the womb, as of the 19th week of pregnancy. In connection with a gene test on the parents, the hereditary disorder can be proven at an early stage.

Further information:

Prof. Dr. Holm Schneider
Phone: +49 9131 8533775
holm.schneider@uk-erlangen.de