I’m Aware That I’m Rare: Eric Austin, MD (470)

phaware global association®
11 min readMay 27, 2024

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the phaware® interview

Dr. Eric Austin, a pediatric pulmonologist and pulmonary hypertension doctor, discusses the upcoming World Symposium on Pulmonary Hypertension, which will focus on various aspects of pulmonary hypertension research and clinical care. Dr. Austin is part of the task force on genetics and genomics, which aims to explore the genetic landscape of pulmonary hypertension and identify opportunities for future research and therapy development. He highlights the significance of the discovery of the BMPR2 gene and its role in pulmonary arterial hypertension (PAH), leading to the development of the gene-informed therapy sotatercept.

I’m Eric Austin. I’m a pediatric pulmonologist and pulmonary hypertension doctor at Vanderbilt University Med Center at the Children’s Hospital there. I direct the Pediatric PH Program. I’m a proud member of several groups that affiliate with pulmonary hypertension research and clinical care, including the Pediatric Pulmonary Hypertension Network.

Today, I’m going to talk to you a little bit about the World Symposium on Pulmonary Hypertension, which occurs this summer, 2024, in Barcelona. This is a conference that’s occurred intermittently since its initial meeting, I believe, in the 1970s. The most recent meeting was about five years ago. So, we’re reconvening as a field to think about different aspects of pulmonary hypertension in children and adults and different forms of both research, clinical care, and opportunities for the future and needs that we still need to fill.

For example, I’m part of the task force on genetics and genomics, which I’m leading with Dr. Wendy Chung. We have several fantastic people in our task force. We’re charged with thinking about where we’ve been in terms of the genetic landscape of pulmonary hypertension, what discoveries have been made, and of course providing an overview to the ultimate readers of the documents that come out of the conference. But also, to think about what’s the next phase? Where do we need to go with genetics and genomics? We have a lot of gene discovery now that has occurred. We’ve had some progress over time in terms of impacting clinical care, but not as much as one would hope based upon other fields that have profound genetic discoveries.

However, we’ve got this exciting new line of study that has been translated from cell-based studies and animal studies and then into clinical trials with the drug sotatercept that is emerging. I’d remind people that that drug and its progression, which was led by several wonderful investigators and then a partnership with industry, they really pursued that because of the initial genetic discovery that the bone morphogenetic protein receptor type two, BMPR2, was not only mutated in a lot of families that have pulmonary hypertension — children and adults with what we used to call primary pulmonary hypertension, but is also not as robustly expressed as a protein in people of other forms of pulmonary arterial hypertension.

Because of that initial genetic discovery of pulmonary arterial hypertension associating in families with BMPR2, it was then discovered that BMPR2 is found in other forms like idiopathic PAH, in particular. Then, people started to look at other types of PAH, and they found that even if a person does not have the mutation, they have low expression of the gene and they probably have some degree of depressed function of pathways related to that gene. So, that triggered many, many years of study that ultimately are culminating now in the first gene associated or gene informed therapy, the sotatercept therapy, that will hopefully be approved by the time we’re meeting this summer.

So, what’s exciting about genetic and genomic therapy to date is that while it hasn’t had a profound impact on our care to this moment, we understand more and more about patients and families who are impacted by gene mutations, but we’ve also had investigators around the world looking at the genes and pathways related to not only BMPR2, but other genes that are now known to be mutated and associated in families. That investigation, that gene informed investigation, has really what has propelled the field toward new therapy opportunities. In particular, as you may or may not know, BMPR2 expression is reduced in the tissue of many forms of pulmonary arterial hypertension.

Because of that reduced expression and probably reduced signaling in the lung of people who have PAH, investigators started to say, “Okay, well, let’s use our genetic information that we understand and let’s try and think of ways that we could improve the function of that pathway or correct its balance in a way.” So the gene discovery informed therapeutic development in a really exciting way that of course now come the meeting this summer in 2024, it’s likely that there will be people getting FDA and EU approved sotatercept, which is a gene informed therapy, I would argue, to correct the balance at the molecular level that BMPR2 is so intimately involved in.

So, an interesting question you might ask is, “Well, so you’re part of the genetics and genomics task force?” There’s lots of task force by the way. There’s a pediatric task force, there’s a risk score task force. There’s many other aspects. There’s a pathobiology task force. The genetic and genomic task force to my recollection, I think this will be the fourth time it’s been included in the conference. What really prompted its initial participation as a task force is because of the genetic discoveries that were happening and people wanted to get informed. So originally, BMPR2 was discovered in the year 2000, published in 2000 by two different groups working across the world. There was actually, truthfully, a little pause thereafter in genetic discovery from about 2000 to about 2008. People were working hard trying to make new discoveries, but they weren’t really emerging as quickly as one would hope.

Then, we started with the emerging landscape of new technologies to survey people’s genome, starting with whole exome sequencing and then going with whole genome sequencing. Of course targeted discovery efforts based upon what we knew about the genes related to BMPR2, including alkaline and enhancin, which of course did come shortly thereafter. I think around 2008 was the first time there was a genomic task force included in the process. The goal at that time was really to just update people and say, “Okay, look, what genes are available? What are on the horizon?”

The other thing that’s challenging for clinicians is that we now think about genetics and genes in our patients much more commonly than we certainly did a decade ago. But it’s hard to know sometimes when you’re boots on the ground in the clinic or in the hospital, which panel do I order for someone? What company or institutional resources do I engage to not only send out the blood and get it evaluated, but also understand the information that comes back? Because unless you’re a trained geneticist, it can be a little confusing. I’m sure patients and families have also seen their reports at times. You’ll have reports that will say, “Okay, we found these seven genes have variations in them that might be classified as mutations.” A mutation, by the way, means there’s less than 1% of the global population who is your ancestry would have that variation in their DNA.

But there are so many variations now with this explosion of DNA analysis that you get a report back as a clinician and a family member or a patient and it will say, “There’s these 12 genes that are different than they should be or mutations.” But the clinical significance of that has yet to be published or determined. So you could have a person who’s maybe the first person who’s ever been discovered with PAH to have that mutation. Does that mean it caused the mutation? Does that mean it was associated in some way that made their PAH develop? Where is the connection there? So, it’s really difficult for doctors and patients and families to understand sometimes those reports.

So, long-winded way to say, one of the charges that we’re going to take is helping people to understand the resources that are available to interpret those findings and do our best to say, “Okay, here are the genes that we really believe are truly, if not causative of PAH, extremely tightly associated with it.” To the point that if you have a mutation in that gene, you should take it very seriously. What we may not be able to do in that task force is go through every mutation in every gene and publish, “Okay, if you get this variation in your DNA and this gene, this means this.” That’s probably a level of detail that will be hard, but try and provide resources for people.

Then, the second thing that we’ve really tried to do, and I’ve talked to Dr. Chung a lot about this, and as our senior lead, she’s really interested in going beyond just gene description, PAH or not, done. So what we’re going to try and do is think about what is the next horizon that needs to be done to use the knowledge that we have already to get to more drug therapy, to get to more understanding of clinical outcomes? Because we do tend to, in our field, tend to make these discoveries but due to limitations of sample size and other things, we’ve not always made the connection. We know that individuals who have certain gene mutations, including BMPR2 probably are diagnosed earlier, probably have worse hemodynamics when they’re diagnosed, probably have a higher risk of right ventricular dysfunction and failure before a given other person, but we don’t have a lot of great data beyond BMPR2 for that information.

One of our tasks is going to be to collect what we do have, analyze it together, and then look to challenge the field for what needs to be done between now and the next world symposium, wherever that is going to be in four to six years.

When we have a new diagnosis, that’s the most common time to initially think carefully about genetics and genomics. We could come back to that, but one thing we’ve started to begin to do is think about revisiting genetics and genomics when we didn’t find anything five years ago. But say you have a new patient and they present unfortunately with what we think is idiopathic pulmonary arterial hypertension, and they have no family relationships that would suggest that they have familial disease, we still in the current era, at least in pediatrics, offer them genetic testing for a few reasons.

One, to make sure that we understand to the best of our ability why they have the disease. Number two, there may be major family-based impacts to have a diagnosis that comes with a risk of heritability or the risk that someone may have received it because they got a gene that was variant from their mom or dad that could have repercussions for other siblings or for future childbearing and whatnot.

So, in pediatrics we kind of grew up as a field even beyond PH, thinking about genetics very carefully. We have that discussion every time with our patients. But what we don’t do a great job of is actually thinking about the cost of that. For our region in the mid and southeast, we have very limited difficulty getting it approved, currently. Almost every insurance company approves the genetic testing interestingly. Generally speaking, aside from the copays or the additional burden of any other test, it’s not an added measure of financial cost to families. Of course, it’s still part of the giant cost of having to deal with an individual who has PAH or other medical problems. To do the current era, a panel is probably about $1,000 charged to the insurance company. It varies by company and whatnot so I don’t know specifically.

If you’re going to look for a panel of genes, and that’s an important point, also. Generally speaking, we have a new individual diagnosed, we offer them genetic testing, we would send off probably a targeted panel looking at the genes that we know are associated with PAH. Within that targeted panel, not every company offers exactly the same panel. So, your physician and you may want to think carefully about which panel we’re doing. The truth is sometimes you don’t have much choice. Oftentimes, there may be negotiated contract relationships by both insurance and your medical facility that force, but that panel tends to be about $1,000.

If you’re in a family that has known PAH and known gene already that’s variant. So, say you’re in a BMPR2 family, maybe you don’t know the mutation, but someone in your medical care world does, that’s a cheaper test, that’s a targeted test. You could say, “Well, we’re not going to bother to send the whole panel out, because we know this family has BMPR2. This is so rare, it’d be weird for them to have another gene.” That’s about 250 to $300. So, some families, especially in the previous era, used to elect to spend that themselves out-of-pocket, because they didn’t want their genetic information for their child to be already dictated at they’re four years old and they already have PAH, which is a challenge, and then we’re going to label them as having a, quote, “mutation”. That stigma has begun in the last five to seven years to really dwindle, thankfully. There are protections for people genetically. Genetics has become so ubiquitous in our care that we don’t have that happen very often anymore that someone just pays out-of-pocket.

So, I’m really excited to continue working with our group on the task force for genetics and genomics for the World Symposium on PH, and also just for the collaborative opportunities and processes that we have going on in North America and beyond already. I think if you’re a family who is struggling with this, one thing you can hold onto with hope is that we are learning so much every day about genetics and genomics. It’s not just about yes, no mutation. It’s now about what are the variations and the pathways associated with these genes and how can people in the bench, and then ultimately those of us translating into the clinics, how can we take either novel therapeutic developments or existing therapies that, oh, it turns out that therapy that has been on the shelf for 50 years actually influences the activity of genes related to the gene that causes my kid’s PH. There’s a lot of work going on to try and figure that out. Sotatercept, as I said, is just one example of that. I think and hope we’re going to have many more soon.

So, this summer is a great opportunity to kind of regroup, think about where we’re at, lay groundwork for what we want to challenge the field to do in the next five years, and really set the stage for the next era of PH therapy, which I think is coming quickly. That’s going to be beyond relaxing the blood vessels, what we call vasodilation, but into modifying the underlying causes. So, we have great hope. Genetics and genomics are just one component of that.

I’m Eric Austin, and I’m aware my patients are rare.

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phaware global association®

Are You #phaware? Pulmonary hypertension (PH) is a rare, life-threatening disease affecting the arteries of the lungs. www.phaware.global