Other groups of viruses, such as adeno-associated viruses (AAV), reputedly produce safer vectors, because they stay outside their host’s genome without inserting their DNA. But they have their own disadvantages. As a foetus’ cells divide, the initial salvo of vectors becomes diluted out. That’s acceptable for slowly dividing tissues, like the nervous system, but it will not work in rapidly dividing tissues like bone marrow.
Once a vector is chosen, it must be guided to the right place. For bleeding disorders, it is a relatively simple matter of injecting the vectors into the bloodstream, via the umbilical cord. For diseases that affect more localised organs, ultrasound can help to guide a needle to the right spot.
As an alternative to injecting vectors directly into the womb, some scientists are looking to correct a foetus’ faulty genes outside of its body – by extracting cells, correcting the genes, and transplanting them back in again. “Then, you’re only targeting the cells that you want to target,” says David. She has already proved that this is possible in sheep, using transplanted cells that contained a simple marker gene. “The next step is to try and cure a genetic disease,” she says.
Case by case
But no matter what the approach, prenatal gene therapy will always involve taking blood samples from foetuses, and injecting vectors or cells back in. “There’s obviously a small miscarriage risk with that,” says Waddington. However, he points out that these injections are far less invasive than foetal surgeries and blood transfusions, which have been used to treat birth defects for several decades.
There is also a variable risk with the imported genes themselves. For example, factor IX clotting factor is not harmful at high levels, and people with haemophilia B already inject themselves with huge amounts of it. By contrast, genes that oversee large genetic networks could cause big problems if they are switched on in the wrong place, or at the wrong levels. In two animal studies, attempts to introduce growth factor genes into the lungs led to build-ups of abnormal tissue. There is also the possibility that the added genes could end up in the mother, via the placenta.
All of this means that every use of prenatal gene therapy has to be examined on a case-by-case basis. The technical challenges will vary depending on the organ being targeted, with each one having a different ideal vector, route of delivery or window of time. And as Waddington says, “You’ve got to look at the safety aspects for every single gene that you’re delivering.”
This is why the first human trials of prenatal gene therapy, when they arrive, will probably involve a narrow range of diseases: those that are otherwise hard to treat, and that cause serious illness in foetuses or newborn babies. For example, babies with the severe form of Factor VII deficiency – a bleeding disorder – invariably start bleeding inside their heads, within hours or days after they are born. The results are fatal. Another blood disorder, alpha-thalassaemia major, kills foetuses before they are even born.
“I think it’s still not completely clear which diseases are the appropriate targets,” says Waddington. “But the feeling I get is that the diseases that are very nasty, very early, are the ones to go for.”
But most genetic disorders are not so clear-cut. Take Gaucher’s disease, a condition where abnormal fatty deposits build up in several organs, causing everything from weakened immune systems to early brain degeneration. It is caused by problems in one gene, but mutations can break the gene in 100 different ways, with varied consequences. Waddington has spent several years working on Gaucher’s and he says, “It’s quite clear that we don’t have a complete handle on the different signs and symptoms and the biochemical readouts of the disease. Some people may go downhill quickly while others surprise you and are relatively well at 10 years.”
This may be one of the larger hurdles standing in the way of trialling prenatal gene therapy in humans. It is meant to be a preventive technique, which averts the damage caused by genetic disorders before it happens. To apply such a risky and contentious strategy, we need to accurately predict which foetuses will benefit most, while they are still healthy and developing in the womb. To prevent, we must first learn to predict.