Developing a fetal gene therapy with Anna David
Developing a fetal gene therapy with Anna David
ANNA DAVID: My name is Anna David (University College London, UK). I'm a professor of obstetrics and maternal fetal medicine at University College, I'm Director of the Institute for Women's Health, and I'm also a consultant in obstetrics and fetal medicine at University College Hospital (all London, UK). And my main area of interest is developing therapies for the fetus, for the mum to try to improve outcomes for both mum and baby.
Segment:1 Gene therapy as a treatment modality.
ANNA DAVID: I think the thing about gene therapy as a treatment modality is that it really targets certain parts of the body.
ANNA DAVID: So the area that I'm interested in is a problem with fetal growth where – fetal growth restriction, where the baby doesn't grow as well as it should do. And one of the big problems causing that is reduced blood supply to the womb. So normally, your blood circulation goes round about 50 mls per minute when you're not pregnant, but when you're pregnant, it goes up to about 500 mls per minute.
ANNA DAVID: And we know when the baby doesn't develop properly, it's because the womb hasn't got enough circulation going to it. And with gene therapy, you can target the circulation, you can target the viral vector or whatever gene therapy you want to a particular tissue – in this case, the uterine artery vasculature – and that can then have its effect locally.
Segment:2 Testing therapies on pregnant women and neonates.
ANNA DAVID: I think it's a real problem that people are worried about testing drugs in pregnancy.
ANNA DAVID: What they don't realize is probably about 20%, or at least, of all women take some kind of medication when they're pregnant, and much of the time, that medication has not actually ever been tested specifically in a pregnant population.
Segment:3 Engaging stakeholders in non-traditional treatment.
ANNA DAVID: One of the ways we were able to convince people to try gene therapy is when you look at drugs that are out there to try to treat the disease, there's absolutely nothing available.
ANNA DAVID: So we know fetal growth restriction affects probably about 8% to 10% of all pregnancies. It's a major cause of stillbirth. It is untreatable. There are a number of drugs that people have tried, so one of them being sildenafil citrate, or Viagra. But the issue is that the drug isn't local. It crosses over the placenta, and it has systemic effects. And when you're only trying to target the uterine artery circulation or even the placenta, you don't really want to have those unwarranted effects.
ANNA DAVID: You also worry that something might go over to the fetus and might cause a problem long term for the fetus. And so that's why a gene therapy approach which you can target and hopefully doesn't cross the placenta at all, or in only minor amounts, is going to be the way forward.
Segment:4 Delivery challenges in gene therapy.
ANNA DAVID: I think the challenges of gene therapy in pregnancy are, number one, to try to get through the barrier. What we're trying to do is target the mom to treat a pregnancy disease.
ANNA DAVID: So we're not giving gene therapy to the fetus directly, we're targeting a pathology in the mother, which has an effect on the fetus. So to get that concept across is quite important. It's also difficult because there are not many pregnancy models of this disease. So there is no gene, there's no single gene disorder that you can say, this mom has this gene, and therefore, they're likely to have a problem with their baby.
ANNA DAVID: So you've got the whole problem of not being able to identify women that might be eligible for trial, which models, which animal models preclinical testing might do. The toxicology as well is a challenge because the regulators are not familiar with toxicology type. So all in all, it's sort of like challenges for gene therapy but plus.
Segment:5 Regulator engagement.
ANNA DAVID: I think you it's good to talk to regulators from the very word go, which is what we did.
ANNA DAVID: So we went to them and we said, "there is this disease, we think it's amenable to a gene therapy approach. It's very, very serious." And when you present the seriousness of the disease and you can really capture that, then you can understand where the regulators are coming from. I think what it enables you to do is to test out different avenues and for them to say, yes, carry on that path or actually, no, that's not what we want and deviate and go on this path instead.
Segment:6 Treating orphan diseases.
ANNA DAVID: So I think at demonstrating that fetal growth restriction was an orphan disease was quite a novel thing to think about. With pregnancy we don't really think very much about treating pregnancy diseases. And I didn't really know much about orphan disease designation before I started. I think it really brings great advantages because you can go to the regulator and you can say, "I have an orphan disease, it's now been defined in this way."
ANNA DAVID: And it gets you past the first hurdle to say this is an important disease and we know what the prevalence is, and please can we talk about therapy?
Segment:7 Remaining questions.
ANNA DAVID: I think the main question is what do the regulators think about giving a mom gene therapy to treat a fetal disease. So we've answered-- we hope, we think-- all the questions.
ANNA DAVID: So we've answered the issue about is it ethical to give treatment to moms in pregnancy. And we've done stakeholder and patient interviews and looked at the legal and regulatory literature about all of this. And so far, nothing has come out and said, you shouldn't be doing this. We've done a lot of reproductive toxicology studies, along the way, which haven't shown any serious concerns.
ANNA DAVID: And we've identified our patient population. And we know from talking to patients that they really want the therapy. So the final step is to present all this package of data to the regulator, including the drug, which is now manufactured, it's vialed, and say, "look, this is our clinical trial protocol, we think we've identified the best patient population. Do you agree with us, and can we go ahead?"
Segment:8 The future of gene therapy.
ANNA DAVID: Well, the next steps for us all to finally get funding to do the clinical trial. We're waiting to hear back from a number of different funding sources and then to apply to the MHRA [Medicines and Healthcare products Regulatory Agency, UK] for ethics approval to actually do the clinical trial in patients. It's really going to be a big step forward if we can agree that some fetal diseases should be treated by gene therapy. And everything that's been done in adults and now moving into neonates, we're talking about really step change in treatment for severe diseases.
ANNA DAVID: [MUSIC PLAYING]