In December of 2016, we shared with you some preliminary data from Dr. Holm Schneider’s study of treating three babies with x-linked hypohidrotic ectodermal dysplasia (XLHED) in utero. Today, we have an extraordinary update that gives us great cause for celebration! Dr. Schneider and his team of investigators have published their groundbreaking research results in The New England Journal of Medicine in an article titled “Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.” We are thrilled to share with you key highlights from their research, what it means for our families affected by XLHED, and the next steps.
What Causes XLHED?
The symptoms of XLHED are caused by a change in the EDA gene. The altered gene does not produce a protein called ectodysplasin A1 (EDA1). This is the protein that signals the normal growth of hair, teeth, skin and certain glands, like sweat and mucous glands, in the body. Research, partially funded by the National Foundation for Ectodermal Dysplasias (NFED), developed a synthetic version of EDA1.
Scientists used this synthetic version called EDI200 to treat XLHED in mice, dogs and then finally infants in the Newborn XLHED Clinical Trial. The latter study conducted by Edimer Pharmaceuticals found that administering EDI200 to infants between days 2 and 14 of their lives was not significantly effective in correcting the symptoms. Because XLHED is a developmental disorder, treating after birth was too late in the process. Dr. Schneider and the other investigators hypothesized that studies were needed to administer the EDI200 at the developmental stage at which the sweat glands and other affected body parts start to develop in the fetus. This meant treating in utero.
The Latest Study
In 2016, two families in Germany asked and were considered for treatment by Dr. Schneider’s team. The mom of the first family suspected the twin sons she was carrying might be affected by XLHED. (Corinna is pictured above with the twins.) She also had an older son who has the condition.
First, the mom was confirmed to be a carrier of XLHED. Second, the German researchers used ultrasound technology to determine that she was carrying twin boys who were both lacking tooth buds. The ultrasound showed that neither had any tooth buds in the lower jaw. One boy had one tooth bud in the upper jaw and the other had two tooth buds. An MRI confirmed these findings and the diagnosis of XLHED for both boys. The mother received injections of EDI200 into the amniotic cavities for each fetus at 26 and 31 weeks.
For the second family, Dr. Schneider administered EDI200 to their son in utero at 26 weeks by amniocentesis. Again, ultrasound had shown lack of tooth buds. This child only received the one treatment because of a limited supply of EDI200.
Overall, the findings are very positive!
How well the EDI200 restored the sweat glands was a key benchmark in determining if the treatment was successful. The news is phenomenal. The twins have a normal number of sweat glands. And the sweat glands are also functioning normally!
They produced amounts of sweat similar to infants who are not affected by XLHED. This is in great contrast to their older brother who does not sweat at all. The third baby who only had one treatment had slightly less sweat glands than an unaffected infant.
It’s extraordinary to think about how this lifelong challenge is removed for them and their parents. No longer do they need to worry about overheating and carrying cooling supplies. The fact that these boys can sweat normally is a huge treatment breakthrough!
The twins each had 10 and eight tooth buds compared to their untreated brother, age 5, who has three teeth and one tooth bud. It appears that the boys will not have the normal number of teeth. However, they do have a greater number, which is very positive. More teeth will allow better growth of their jawbone. This should improve their bite force, decrease the likelihood of needing a bone graft and help them sustain dental implants down the road, if needed.
At the time of the report, the twins were 22 months and had not had any respiratory-related hospitalizations. Many of our little ones with XLHED often suffer from pneumonias, respiratory infections and hospitalizations. Eliminating those issues is definitely a treatment success!
The twins produced a normal amount of saliva. This is great as restoring saliva will help with digesting food in the mouth, protecting enamel on teeth and with swallowing.
The twins had more meibomian glands in their lower eyelids than their untreated brother. These are glands on the rim of the eyelid that produce an oily substance which helps prevent tear fluid from evaporating. Having an increased number of meibomian glands should help prevent dry eye problems.
EDI200 did not have any effect on hair. Given the early time point at which hair develops in the human fetus, this was not a surprise.
Relaunching The Clinical Trial
These findings provide us with great hope that the prenatal treatment does correct many of the symptoms for XLHED. However, we understand that this was a small study that involved only three babies. The next step is to conduct a study on a larger number of babies.
We are excited to report good news on this front as well! The EspeRare Foundation announced today that it is relaunching a clinical trial to establish the in utero protein therapy of XLHED as a safe, viable and effective treatment. Based in Switzerland, EspeRare is a nonprofit organization whose mission is to overcome roadblocks that prevent new therapies to reach rare diseases patients.
Caroline Kant, Founder and CEO of EspeRare, said that they have entered into an agreement with Edimer Pharmaceuticals for EspeRare to receive the full rights to continue the development of an innovative therapy for XLHED. EspeRare has renamed EDI200 as ER-OO4.
“This is such an exciting time for the EspeRare team who is preparing to relaunch the clinical development of ER-004 in the coming months, bringing back hope and aiming to provide very promising outcomes for the XLHED community. With this program, not only does EspeRare have the opportunity to bring to patients the first ever therapy that can address a genetic disease during pregnancy, but it also has the power to shift the rare diseases drug development paradigm, opening a new pathway to diagnose and correct other genetic diseases before birth.
EspeRare plans to launch the trial in the first half of 2019 with the ultimate goal of bringing this treatment to market! According to EspeRare, “these efforts will benefit from the European Medicines Agency’s (EMA) PRIME (PRIority MEdicines) scheme, due to the rarity of the disease, the absence of alternative treatment options and the encouraging results obtained in babies treated prenatally by Prof. Holm Schneider.”
Essentially, this means that the EMA will provide enhanced support to the clinical trial. Our Board of Directors, Scientific Advisory Council (SAC) and staff are committed to continue working with EspeRare and offering support as needed.
Dr. J. Timothy Wright, a member of our SAC, has helped steer our XLHED research program for decades.
“Since discovery of the cause of XLHED in 1996, there has been an ongoing effort to find a potential treatment,” Dr. Wright said. “Development of a fusion protein to replace the non-functional protein in the early 2000s showed great promise when used to treat mice and dogs having genetic alterations similar to humans. Since that time, there have been a series of human studies indicating the treatment is safe. This most recent report is the first to describe an intrauterine therapy to replace the protein from a genetic abnormality and demonstrates the tremendous promise for treatment of XLHED using this approach. It is extremely exciting.
According to EspeRare, ER-004 is the first and only treatment specifically targeting XLHED. Administered at the right time during fetal development, it has the potential to become a “single course” treatment, effectively switching off symptoms of the disorder throughout patients’ lives.
Thanking Those Who Paved the Way
Dr. Schneider will continue to monitor the three babies his team has treated. We, the NFED, have awarded $75,000 to him to fund this important work.
We are enormously grateful to Dr. Schneider and his investigative team for being tenacious in their efforts to give our families affected by XLHED a treatment to help correct their symptoms. We salute the two families who stepped forward to be a part of this ground breaking study. Their willingness to participate helped us confirm what we learned in the mice models research: that indeed, the prenatal treatment of XLHED with ER-004is a viable treatment.
They are not the only families who are the heroes in this story. Rather, this research success rests on the shoulders of thousands of XLHED families who have participated in studies for the past 30+ years. Families who literally gave blood, hair and skin samples, who completed surveys, and who volunteered their infants for the phase II clinical trial. They did their part in the faith that a future generation might benefit from a treatment. And that treatment is closer than ever before.
Sarah Yaroch, who participated in the Newborn XLHED Clinical Trial, said Dr. Schneider’s results make her hopeful.
“I’m happy these three won’t have to struggle as much. We participated in the clinical trial knowing our son might not benefit. We did it to help the research. If we had anything to do with this new success, we are thankful we could help. We are thankful to the people before us who volunteered for research, the adults who were treated first to be sure the treatment was safe. There are so many players who helped us get to where the research is right now. Everybody took a part!”
We especially thank all of the donors who supported the NFED for three decades to be the driving force in XLHED research. You can share in our pride in this achievement we have accomplished together! We hope that we can continue to count on you. Consider supporting our Impact Cures, Now! Campaign to raise funds for this critical research for XLHED by donating.
And of course, we must thank our founder, Mary K. Richter, for having the vision for our research program. Her decades of leadership were paramount in getting the research world interested in this condition.
The journey to this point has been up and down but we have always moved forward with optimism and unwavering commitment. The path moving forward will likely be the same. We know that we still have many years to go and successes to be had before this treatment is available for families. But, we will keep moving forward!
For today, join us in celebrating this research milestone and the hope it provides our ectodermal dysplasias community!
Ectodermal dysplasia can cause a lifetime of challenges. By supporting research, you expand early diagnostics, treatments, pathways toward cures… and hope!
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You can also watch and listen to my announcement on this Facebook Live video.