Breakthrough! Gene mutations can be treated before birth

At the first sight of her child, Ms. Sarah Yaroch felt bad. Her father and nephew are suffering from certain diseases. She now sees signs of her newborn son, Andrew: Andrew has no eyebrows, no hair, and the skin looks pale. Mutations make him lack specific proteins when he develops in the womb, causing the body unable to develop normal sweat glands, teeth, and other organs.

Two weeks later, the doctors injected an experimental protein into Andrew’s tiny veins. It is hoped that entering this molecule after childbirth can compensate for something lost during pregnancy.

Two years later, in 2016, the clinical trial suddenly stopped – the data show that this therapy does not work. The two companies that studied the molecule subsequently stopped doing business. Newly-born children like Andrew could not do anything about the disease.

But now, researchers have suddenly heard good news and announced that they have found a way to make this protein molecule work. The answer is simple: Inject drugs into amniotic fluid during pregnancy.

Recently, a paper published in the New England Journal of Medicine showed that the protein has achieved promising results in the treatment of small children with three children. This not only rekindled hope for other children carrying the mutation, but also opened up treatment of hereditary diseases with drugs in the uterus.

Stranded

This rare disease is referred to as x-endocrinological droopy skin dysplasia, abbreviated as XLHED, and affects 1 in 17,000 people worldwide. The most severe patients will have no sweat glands, which may be life-threatening because it cannot discharge heat.

Evidence shows that alterations in the EDA gene are causative for XLHED. This gene encodes the Ectodysplasin-A1 (EDA-A1) protein, which is found naturally in healthy people and is involved in the formation and development of skin and teeth. But in individuals with XLHED, EDA-A1 is lost due to an alteration in EDA. Thus, scientists have developed an EDA-A1 replacement protein (EDI200), which is a recombinant protein, and tested whether it could reverse the development of XLHED.

In 2016, Edimer announced that clinical trials for newborns of XLHED did not meet expectations. In the trial, the children received ED1200 protein therapy shortly after birth and the results showed that the symptoms were moderately improved. However, no significant changes in sweat gland function, teeth, and no other early markers were seen. The trial was terminated due to failure.

Transfer

In December 2015, Professor Holm Schneider of German pediatrics received a phone call from Ms. Corinna. She had a son with XLHED and was pregnant for another about 14 weeks. She suspects that the fetus will also be affected by the disease and specifically seek help from Professor Schneider.

Prof. Schneider from Germany was one of the main researchers in the initial phase of the clinical trial. At the time, he was testing the drug on neonates. The results were not optimistic – infants taking this drug would still not sweat. He believes that the reason for the failure is that postnatal administration is already too late and therefore cannot affect the development of sweat glands and other key markers. If injected into the uterus, there may be better results.

Professor Schneider hopes to start clinical trials as soon as possible, but he knows that regulators and ethics committees are very difficult to pass human studies on fetuses and newborns. Gene abnormalities have been corrected when proteins are injected into pregnant mice’s blood and amniotic fluid. However, it is impossible to repeat the same experiment immediately in humans. Therefore, he and the team first confirmed the safety of the drug in adults carrying the mutation.

The next part is the hard part. After all, the development of mice and dogs in the uterus is very different from that of humans. With the help of patient groups such as the National Foundation for Ectodermal Dysplasias, they began to look for pregnant women who carried the mutation and wanted to know if they would be willing to let the child be treated immediately after birth.

After receiving the phone, Prof. Schneider can only promise that Ms. Corinna could go to diagnose whether the infant has XLHED by ultrasound during the 22nd week of pregnancy. Unfortunately, the result is positive.

A few weeks later, they made a joint decision to inject the drugs left after the last clinical trial into Corinna’s pregnant abdomen. During the 26th week of pregnancy, the doctor drew a little amniotic fluid and injected some medicine. After a few weeks, another drug was given, and then Linus and Maarten were born ahead of the cesarean section and were twins!

Miracle

On the forehead and nose of the newly born twins, sweat was clearly visible. Through the microscope, the number of sweat glands on the soles of their feet is normal! Unlike their sick brother Joshua.

If these tests are only targeted at certain body parts, they cannot explain all the problems. In the summer of that year, when parents saw the twin boys sweat soaked in the car seat, they were very excited about the effect of this treatment! They took a picture and sent it to Professor Schneider. Ms. Corinna recalled: “It’s amazing to be able to save sweat. It’s incredible. It’s incredible.”

Another XLHED child’s family had heard of the experiment and asked Professor Schneider if he could receive the same treatment. The professor agreed, even though there was only one dose of medicine left in the refrigerator in his lab. After the baby was born, he had 9 sweat glands, which was slightly less than normal, but better than his 2-year-old brother (only 2).

Future

At the time, after Edimer’s failed trials of this protein for neonatal treatment, investors thought the drug was worth continuing research and development. It was the insistence of Prof. Schneider and the team that they did not give up, continued to study, and later had treatment for 2 pregnant women, which eventually changed the fate of the 3 children. Dr. Kirby, Edimer’s CEO, was very excited about the three cases of successful drug treatment before birth.

Now, researchers are planning to conduct more extensive clinical trials with the help of a non-profit foundation that will take over drug development. This may involve new challenges, such as clinical ethical issues – who is the patient? An expert who turned from a geneticist to investing said: “You need to find pregnant women who are not pregnant and carry mutations and develop a drug to treat those who have not been pregnant. This is really different.”

For those parents who participated in clinical trials after their child was born, this new study also made them happy. Ms. Yaroch said: “This drug does not work for my child. I am not sad. On the contrary, I am grateful that the scientists are still studying this issue because if the test is terminated, my grandchildren may also get this disease, and there is no cure.”

Alisa Wu is a writer and working at the biotech company Cusabio that manufactures recombinant proteins and offers custom protein expression services. She regularly writes and shares articles about scientific research, biotech, and other related topics.