A new wave of medical treatments are being used to re-engineer fetal bodies, countering the effects of serious genetic conditions before a child is even born. In a landmark result, several children have been treated for a condition that causes almost no sweat glands or teeth to develop. The innovative “intrauterine protein therapy” partially restored these missing body parts, the first example of any drug treatment building new anatomical structures before birth.
The approach is a twist on the kind of gene therapies already being used to treat children and adults for serious conditions such as the blood-clotting disorder haemophilia and spinal muscular atrophy, a progressive and often fatal form of paralysis. Such therapies make permanent changes or additions to DNA, ensuring that cells make the correct versions of the protein involved in the condition.
While giving gene therapies before birth may be even more effective, scientists have long been cautious about using medical interventions on fetuses, because of the huge potential for something to go wrong. So rather than altering genes, intrauterine protein therapies involve delivering the correct version of the protein that a faulty gene is supposed to make (see “Different fetal therapies”, below).
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The idea has been put into practice by at University Hospital Erlangen in Germany and his colleagues. They have used protein therapy to treat ectodermal dysplasia, a condition which, in a severe form that mainly affects boys, means they have no sweat glands, very few teeth and sparse hair.
The worst aspect is the lack of sweating, as this can be fatal in young children, and even adults with the condition always need to be careful not to overheat, says Schneider.
The condition is caused by mutations in the gene necessary for the formation of sweat glands, teeth and hair. The protein this gene codes for needs to be delivered between about 5 and 7 months of pregnancy. “If we miss this window, then we will not be able to induce sweat glands later on,” says Schneider. That also means the condition can’t be treated by gene therapy post-birth.
His team has previously reported treating six boys with the condition, and he has now begun a formal trial. In the first six cases, five who received two or three doses of the protein were born with the appropriate number of sweat glands, while one who received just one dose has somewhat fewer glands, but he still has good heat tolerance, says Schneider.
The oldest of the treated boys are twins, now 7 years old, whose sweat glands are functioning well. They coped fine with a medically supervised trip to a sauna, Schneider reported on 17 June at the (IFeTIS) Conference in Edinburgh, UK.
The treatment also led to more teeth developing. Affected children usually have three or four teeth, all in the upper jaw. The treated boys have an average of 10 teeth in total, across both upper and lower jaws, which will let dentists fix prosthetic teeth to the natural ones, says Schneider. “That’s a very big advantage.”
“They have done the first intrauterine treatment of a genetic disease with a genetically focused therapy,” says at University College London, who organised the IFeTIS conference. “Definitely it’s a landmark.”
Schneider’s team delivered the protein by injecting it into amniotic fluid, which fetuses regularly swallow. The protein was linked to an antibody that the fetal gut normally absorbs well, as it is designed to take up antibodies present in breast milk.
The same technique – of fixing a therapeutic protein to this antibody – could be used to treat other conditions, says Schneider. His team is investigating turning this into a treatment for cleft palate, where the top of the mouth doesn’t form properly.
In a second example of intrauterine protein therapy, at the University of California, San Francisco, and her colleagues have made progress with treating a group of metabolic conditions that, if untreated, can be fatal in childhood. For instance, in one form, called , babies lack a working version of an enzyme, which leads to heart damage.
The enzyme is currently given as a treatment after birth, but by then, some of the damage is done. Mackenzie’s team has now injected the enzyme into the umbilical cord of three fetuses, the researchers reported on 19 June at the , also held in Edinburgh.
The team reported in December that the first child, now aged 1 year, has excellent heart function and is meeting developmental milestones. The other two individuals have been born and are “doing well”, says Mackenzie, although she isn’t yet giving further details.
Protein therapies aren’t the only example of prenatal treatment taking off. Researchers are also looking at using stem cells, which are similar to cells in an early embryo and can multiply and grow into different tissues. If stem cells without a faulty gene are given to a fetus, the aim is that they will take up long-term residence and substitute for the recipient’s cells with faulty DNA.
One promising application is as a treatment for brittle bone disease, caused by mutations in the genes that make collagen, a constituent of the skeleton. In the severest versions, people have a twisted skeleton and may have several hundred bone fractures in their lifetime. “You can imagine the pain,” says at Karolinska University Hospital in Stockholm.
Stem cells may be a better treatment for brittle bone disease than gene therapy, as the condition can be caused by mutations affecting multiple genes, says Walther Jallow, which means each one could require a slightly different gene therapy design. However, people may need to receive several doses of the stem cells.
In this case, the cells being used come from aborted fetuses. They are a kind known as mesenchymal stem cells (MSCs), present in many organs of the body. When injected into the blood supply, they take up residence in various tissues and turn into that tissue – including bone, animal studies have shown.
Walther Jallow’s team has been using MSCs as a treatment for brittle bone disease when given to young children. They have also given them to four fetuses under “compassionate use” rules that apply in desperate medical cases. Encouraging results were reported for the first two individuals, who seemed to have fewer fractures and better skeletal growth .
A trial is now beginning to compare results when the cells are given as several doses after birth, or in some cases prenatally as well. This has so far treated an additional three fetuses, as well as 15 children after birth, Walther Jallow reported at the IFeTIS conference, although results aren’t yet available.
The first compassionate use of stem cells for brittle bone disease in a fetus was 20 years ago, yet the formal trial only began in 2020, showing how slow-going the fetal therapies field can be. Researchers want to avoid unexpected toxicities, such as has happened with some gene therapies given after birth, says Mackenzie. For instance, in the early 2000s four children being treated for a rare immune condition developed leukaemia as a result.
A shadow has also been cast over the field by the 2018 scandal in which He Jiankui gene edited early embryos in an attempt to give people resistance to catching HIV. His actions led to three girls being born with permanent changes, not only to their own cells, but also to the “germline cells” that give rise to eggs within their ovaries, meaning that their descendants will be genetically changed too. He was jailed by Chinese authorities but has since been released.
The priority is to ensure no such further germline changes are made, says Mackenzie. “We’re very careful to separate ourselves [and show that] what we’re trying to do is not create heritable changes in that family’s bloodline.”
Nevertheless, with the first trials having begun for stem cell and protein therapies, and several gene therapies already approved for children after birth, Mackenzie predicts that fetal gene therapies also may not be too far away. “Right now, we’re probably at the inflection point,” she says. “We’re all trying to be very circumspect and cautious. But we’re excited about the future.”
Different fetal therapies
Medical conditions caused by faulty genes can be tackled in several ways:
Gene therapy – Cells in the relevant part of the body can have a correct version of the gene introduced or, more recently, the DNA can be changed using CRISPR “gene editing”. A few such therapies for adults have reached the clinic, but as a fetal therapy, techniques haven’t yet moved past animal tests, with the exception of the “CRISPR babies” scandal in 2018 (see main story).
Protein therapy – Instead of editing DNA, the correct version of the protein encoded by the gene can be given to the fetus. This has been done successfully for two medical conditions, one that causes a lack of teeth and sweat glands, and a usually fatal metabolic disorder.
Stem cell therapy – Stem cells without the faulty gene are given to a fetus, with the aim that they will take up long-term residence and substitute for the recipient’s cells. This has helped several children with brittle bone disease and a trial is ongoing to treat alpha thalassemia, which requires frequent blood transfusions.
