Drs. Matina Prapa and Olivier Danhaive - phaware® interview 559

How a Global Team Is Rewriting the TBX4 Playbook

Rare diseases thrive in isolation. TBX4Life is changing that. In this episode, Drs. Prapa and Danhaive share how international collaboration is creating real-time change for patients. From newborn screening to natural history studies to rethinking how we talk about genetic testing, they’re helping create a
roadmap to a cure.

Matina Prapa, MD, PhD:
Hi, my name is Martina Prapa. I’m a clinical geneticist. I work in London, at few centers, St. George’s and Royal Brompton Hospital. I’ve been a geneticist for three years now as a consultant. I stumbled into the world of pulmonary hypertension as a trainee in clinical genetics in Cambridge. That has created a big connection for myself in terms of TBX4Life, because I studied the association between the genetics of TBX4 and the manifestations of the condition itself.

Olivier Danhaive, MD:
I’m Olivier Danhaive. I’m Belgian. I’m a much older, I’ve been 30 years plus in neonatology. I’m a neonatologist trained in Belgium and in the US and worked in Italy, and the US and in Belgium. Now, for the past five years, I’ve been the Director of Neonatal Intensive care in Brussels at Catholic University of Louvain. So, that’s my work. I always was intrigued clinically by those infants or children or newborns with rare diseases with special conditions that we would not necessarily understand. They were really a trigger to my scientific curiosity. I came into getting interested in lung disorders, especially because they were pretty challenging to manage.

We started to explore the genetics of lung disorders and understand that there’s many types. Some are problems of development, their lung lacks a piece or has some malformation. All of these connects to certain genes and certain mechanisms. I came into one of the first patients who was affected with a manifestation of the gene TBX4, which we didn’t know at that time because it hadn’t been really described as a disease. That really hit my memory and it triggered an interest in collecting and finding among my colleagues and collaborators, more and more cases in order to get a better understanding of this disease.

Matina Prapa, MD, PhD:
It was serendipitous. I was introduced, I don’t remember how it came about, but I became a member of TBX4Life when it was in its infancy. They were looking for volunteers to take on the management of the working groups. I just raised my head and I said, “Happy to do it,” because no one else was really volunteering. I was quite junior, but I thought maybe that’s my way into a leadership role, as well. The team is lovely, but to be honest, I was struggling with the admin workload and trying to manage the whole thing on my own. We worked quite nicely with Olivier and at some point I just ask, him, why don’t you join me? It’s very nice energy because we’re coming from different fields, different countries, different levels of experience, but it works quite well. So, that’s how we met each other. It was online, but now we’ve been through a few meetings. I met you in Cambridge, as well?

Olivier Danhaive, MD:
Right. Right. Well, I came late in the group. I just joined a couple of years ago, because some of the people I had collaborated with in the US became members of TBX4Life in particular, the people from the PPHNet group, Steve Abman. They said, “Olivier, by the way, you wrote that paper that we are all talking about because it’s kind of described the phenotype of newborns. Why don’t you join?” I was really happy to come in. That’s how I came across Matina, which I had met before, actually. But we started working in her working group and as you said, at some point, we kind of shared a little bit the driving of this group, trying to get things moving, advancing knowledge and science because that’s what we’re have for.

Matina Prapa, MD, PhD:
I would say we’re very international, with a lot of centers mostly across Europe and the States. We have two working arms at the moment, clinical and basic science. So, the people who do the lab work and the people who are more patient-facing. But we do speak to each other a lot. We’re both working towards particular goals. We can talk a little bit about what we have been doing. One of the things that we stumbled upon and understood is that people struggle with, they get a diagnosis, where do we go from here? So, essentially the number one thing we want to do is to draft some guidelines or recommendations so that you can pass on to your physician and say, I’ve got this rare condition, this is what we should be doing moving forward. So, that’s our number one goal at the moment.

But there are lots of other things that we want to address. One is we want to complete a natural history study, because we know there’s huge variability even within families with the exact same gene change. That might give us a better idea for future clinical trials in terms of modifying genetic factors. For example, why someone, a father is unaffected but the child is severely affected, vice versa and take it from there. These are our two main focuses. From the basic science perspective, there’s a lot going on with mouse models, cell lines, et cetera, which complement the clinical work quite nicely.

Olivier Danhaive, MD:
One pitfall for the families and for ourselves, as well, is the journey that it takes from when the disease manifests itself to when you get a diagnosis or cause. In my feeling, in my perception, and talking to so many families, that’s so hard to have questions in your head about a son or a daughter or a family member. You see that something is serious, something is happening, something is progressing and you don’t know what it is. Maybe the doctor doesn’t exactly know what it is either. That’s really one of the biggest challenges in rare diseases in particular with pulmonary hypertension, because pulmonary hypertension is a rare disease and there’s not that many people who know about it. To know how to really untangle the genetics, the clinics, the treatments. Also, the second challenge with TBX4 is that it’s a disease that has so many shapes and facets.

Sometime, you can get an orthopedic disorder kind of toe problem or knee problem and be perfectly fine. Others have pulmonary hypertension, which is very severe. It’s a big burden in terms of health. That can happen at several different ages, different periods of life. For each of these manifestations, each of these ages, you have different doctors, different specialists who don’t necessarily talk to each other. That may be the biggest step that’s been brought by something like TBX4Life, because now I would say independently of TBX4, if I had a newborn in my unit with a challenging disorder I don’t understand, I have a community of collaborators I can call immediately. We have a network and we exchange knowledge and I know exactly who knows what and who can help me with what. That’s a fantastic achievement.

Matina Prapa, MD, PhD:
Patients and families rarely say no to genetic testing, but obviously when you do consent them and explain why we want to do the test, you have to explain the pitfalls, as well. There are several negatives or potential pitfalls. One is the results of the test. We always say to families are not black or white necessarily. It could be a gray result, the so-called variants of certain significance, which we’re burdened with in genetics. That can be difficult for the family to cope with and understand what it means. Sometimes, it’s the sense of guilt. So, especially if you find a variant, by variant I mean a gene change that was inherited by a parent. So, there’s some guilt.

We always say to parents, “Look, we all pass on things to our children and it’s a matter of bad and good luck really. Sometimes, you just don’t know. But the silver lining is you can do something about it now.” Then, of course, the upside is that families, they find it so helpful to actually have a name or be given a diagnosis. Sometimes, it’s very difficult because they say, “Okay, now what? Is there a cure? Is there a gene therapy?”I think we’re moving towards that slowly, but there’s still lots of things you can do in the meantime to try and optimize treatment.

Olivier Danhaive, MD:
First of all, I would say in the past 20 years, the number of disorders for which a causative gene has been identified has been multiplied by 20–30 (times). It has really been a boom due to the natural progress of medicine, also by the incredible progress of technology. When I started, you would sequence a gene like you would read a book, like it would literally, there was a machine would read beat by beat by beat each component of one gene. Now, you just blast the whole genome and you get a printout of what’s in. So, there’s been totally an acceleration both on diagnostic and research on that field. Then, genes are being repaired and replaced now. I mean it happens, it really happens. It’s still dawn. I mean it’s still the beginning, but you have disorders that were otherwise lethal and they’re not lethal anymore. So, you can really cure genetic disorders. When you think about it, it’s kind of magic.

Matina Prapa, MD, PhD:
It’s a very exciting field, massively exploding in terms of massive parallel sequencing, which is what Olivier was talking about. You can sequence someone’s entire DNA within a space of a day. Problem is, you’re left with so much data that you can’t necessarily interpret it. You have to be quite cautious in terms of how you read this genetic data and how you interpret it. As you know, there’s been massive explosion of direct-to-consumer testing, as well. Which, again, is not necessarily helpful. I think this is where I see a little bit of, not of distrust, but misinformation I would say from families, that they go and have 23andMe or something else done and then they come to you and they expect to get some answers for genetics that we know that don’t really contribute to a condition like early onset Alzheimer’s or hypertension, for example.

But for the ones that we know, there is a good association between a single gene change and the condition, we’re on the frontier of gene therapies. We have the tools. It’s the matter of how to deliver, how expensive and how fast it’s to actually develop those therapies and get them to the patient. I can’t speak for the US, although I know that from experience, there are lots of people who have access to genetic testing it seems like. I can speak for the UK. It’s one of the frontiers of the so-called whole genome sequencing, which is what I mentioned, just reading everyone’s whole DNA, the entire genome in the national healthcare system, for free for the patient for several indications.

I think what the desire is for the UK at least, is for every single patient who comes to the national healthcare system is to have their whole genome sequenced. Obviously, this is for research purposes as well, not just for diagnostic purposes, because they want to build a library where we can carry on studying the genetics of people and try and unmask new conditions, as well. I don’t know about Belgium, but you’re quite advanced as well, aren’t you?

Olivier Danhaive, MD:
Well, Belgium, it’s not such an ambitious nationwide program, but we do have labs and universities and tools. Belgium is really fragmented as a country, but that’s the way it is for pretty much everything from politics, to medicine, to research. But I would say in terms of cost, it’s now totally in the same magnitude as any test. In terms of sheer costs, technical costs, I mean getting an exome sequencing, it’s a little bit more expensive than getting an MRI. So, it’s just mainstream medicine.

Matina Prapa, MD, PhD:
We tried to formulate a road map for the next three and five years, which is a timeline of what we want to be achieving, what’s realistic, what’s unrealistic, where will the funding might be coming from, et cetera. I think this is where we are at the moment. Obviously, Anton Morkin who is the CEO and founding member of TBX4Life, he wants a cure and that’s where we are supporting him and we’re putting all of our money in terms of efforts. How close are we to that? Not very close, but there’s amazing basic science research going on, approaching it from right and left, not just on TBX4, but generally for pulmonary hypertension. I think we will be seeing more in the next couple of years.

Olivier Danhaive, MD:
Sometimes the gap between science and actual patient treatment, the gap may be wide, because there’s so much regulations. It’s not only that you need to invent the therapy, but that you need to validate it, you need to sort it out to go through a whole series of approval and tests. That takes years, if not decades, sometimes. So, that can be pretty discouraging. If you find out that a compound, like a drug, like a molecule could be a good candidate to help people with TBX4, let’s say. So, you really need to go, getting this laboratory compound into a pill or an IV drug that does not take five to 10 years.

Instead, if you test existing compounds, very massively, you test like 10,000 compounds on a single chip, for example, and you find some existing drugs that are used in cancer or in cardiac disease or whatever are actually active. This is the shortcut because it already has an identity. It’s already been tested, it’s already used in human, you can actually buy it. These are incredible shortcuts. That’s the kind of approach we’re looking into at this stage as a transition to real genetic cure, which will clearly take more time. So, I think there’s very exciting things, not only for the beauty of science, but literally for people, for people who maybe are already born or already affected now and, if not, really the ones who are coming in the coming days or months or years. I think we are close to be able to offer some new things.

Matina Prapa, MD, PhD:
TBX4 is quite a tricky gene, because it’s what we call a transcription factor. It switches on and off several of other genes. That’s where the tricky bit comes from. It’s not just about replacing it, it’s about what it does and at what point in time it should be happening, in utero when the baby’s developing in the womb, is it too late if you try and do something five years down the line, et cetera. These answers we don’t have yet, but that’s what people are trying to get to.

Olivier Danhaive, MD:
What is striking here is that every bit and piece of information, everything that one person, one researcher does, comes together for the final purpose. Like Martina was mentioning, doing the natural history project. So, really describing what happens. Put all the individuals with the TBX4 gene mutation, which can go through a terribly sick little baby to a 40-year-old who’s perfectly healthy, is just being tested because he has a family member who’s a carrier. Having all those listed together, we can really kind of get a sense of the disease and that’s extremely helpful, not only to design future therapies, but also to understand what’s going on, how the gene and its mutation impacts health or not. So, I think the fact of putting people from so many different horizons is really what makes it stimulating and great. Thanks for listening. My name is Olivier Danhaive.

Matina Prapa, MD, PhD:
And I’m Martina Prapa. And we’re aware that our patients are rare.

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