Treating inherited disease could start in the womb
For a baby born with genetic disease, a lifetime of treatment can ensue. But research in mice suggests that treatment for haemophilia – and maybe other inherited diseases – could start in the womb, boosting the success of therapies after birth.
Our immune systems are pretty good at identifying and destroying foreign material. Once we’ve encountered a particular invader, our immune cells mount a quicker response should it ever turn up again. This is the rationale behind vaccinations.
But this mechanism can cause problems when we want the body to accept foreign material in, say, the form of a donated organ. But this isn’t always the case. In the 1950s, a group of researchers at University College London discovered that exposing the immune system to foreign material in the womb can have the opposite effect.
The team was grafting skin from one strain of mice to another. The new skin tended to get destroyed by the recipient animals’ immune systems. But when the group injected cells from the donor mice into developing fetuses, the mice that were born were much more likely to accept the skin graft. It seemed they had been primed to the foreign cells while in the womb, and developed a tolerance.
Damaging defence
Sébastien Lacroix-Desmazes at INSERM, the French national institute of medical research in Paris, and his colleagues wondered whether triggering this priming effect might help treat inherited conditions, such as haemophilia.
In haemophilia, genetic mutations cause a lack of blood clotting proteins. The most common type is caused by a lack of coagulation factor VIII. People born with the disorder can be given injections of factor VIII, but the immune systems of about one-fifth of people with haemophilia develop antibodies that render the protein ineffective.
To see if priming in the womb would make any difference to this immune response, Lacroix-Desmazes’s team attached parts of factor VIII to another protein that enabled it to cross the placenta between mother and fetus. The group then administered this to pregnant mice lacking factor VIII. Other similar pregnant mice received no treatment.
Once the pups were born, the team treated all of the offspring with a factor VIII therapy. The mice treated while in the womb were much more tolerant of the protein – on average, their immune systems produced 80 per cent less antibody against it than the control mice.
Black box of development
The team hopes that a similar approach could be useful in other disorders caused by a lack of a protein, such as Pompe disease – a rare, potentially fatal inherited disease characterised by muscle weakness and heart defects.
We are still some way off using these therapies in people, says Mike McCuneat the University of California, San Francisco. We don’t know the ideal dose for a fetus, when it should be used or whether it would have any untoward effects on either the mother or the baby, he says.
"We know precious little about the immune system of the human fetus and the human newborn," says McCune. "The third trimester is a total black box of human fetal development, because we have no way to study it."
Sing Sing Way, an infectious disease physician and scientist at the Cincinnati Children’s Hospital Medical Center in Ohio, agrees that it is early days. “The study shows that this approach can work in mice, but does little to say how it may actually work as a therapy or preventative strategy for humans.”
However, both say exploring the idea of fetal immune therapy is worthwhile.
"If you found a safe way to do this, you could imagine developing treatments for allergies," says McCune. People can be genetically predisposed to allergies, and allergies developing in childhood are a huge problem, he says.
Other autoimmune disorders, including type 1 diabetes, which has a genetic component, could also represent a target for this approach, says Way, so it is potentially of enormous value.
Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.aaa1957
