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Conversations in Pulmonary, Critical Care and Sleep Medicine by the American Thoracic Society
Ugo: [00:00:00] Welcome back to ATS Breathe Easy podcast here on location at the ATS International Conference in Orlando, Florida. I'm Dr. Ugo Ezeama. Today, we are talking about a disease most people have never heard of, and a study that could change how we think about pulmonary fibrosis far beyond the patients it was designed to help.
Hermansky-Pudlak syndrome is a rare genetic disorder. It causes albinism, bleeding problems, and in certain subtypes, a progressive, devastating pulmonary fibrosis. This tends to hit younger adults and moves fast. There's no FDA-approved treatment, and lung tran- lung transplant is the only cure. And for decades, we haven't had reliable blood-based tools to help tell us when fibrosis is coming before it's already doing damage.
That may be changing. A study just published in the American Journal of Respiratory Cell and Molecular Biology used a multi-omics approach to [00:01:00] identify two blood biomarkers, choline and CCL22, that can predict the progression to pulmonary fibrosis in HPS patients. And the implications may extend well beyond this rare disease into progressive fibrosis much more broadly.
I have two guests with me today who bring very different but equally essential perspectives. Dr. Resat Cinar is the senior and corresponding author on this study, leading the section on fibrotic disorders at the National Institute of Alcohol Abuse and Alcoholism at NIH. And Donna Appell in the-- she's the founder and executive director at the Hermansky-Pudlak Syndrome Network.
She has spent decades building the bridge between the HPS community and the researchers trying to help them. Thank you all so much for joining me, and uh, welcome to the show.
Donna: Thank you for having us. Thank you.
Ugo: Donna-
Resat: Thanks for having us today.
Ugo: Yeah, of course, of course. Donna, before we get into the science, I want people to understand what [00:02:00] this disease looks like for the families that you work with
Donna: I, I just wanted to mention that hearing you with the introduction brought me to tears 'cause I am so excited about this breakthrough, um, for us that I almost couldn't...
I have to pull myself together. But Hermansky-Pudlak syndrome, um, is very difficult for our patients. Um, certainly they're born with the albinism. They have legal blindness. They, um, you know, can't drive. They can't, um... You know, they have to struggle reading. Um, thankfully, we have a lot of tools that can help them.
Um, but then they have on top of that the bleeding disorder. Mm-hmm. So these children, you know, suffer from, you know, bad nosebleeds and, uh, you know, there's a lot of episodes. Uh, they have to watch their activities a little bit. And certainly, um, the young ladies and menstrual periods are very heavy. So they have a lot to deal with.
We have 11 different [00:03:00] genes, HPS1 through 11, and it's absolutely a fact that in HPS1, 2, and 4, 100% of the time they will develop pulmonary fibrosis. And it's, you know, not a matter of if, it's a matter of when. So these children and these people are born with a genetic crystal ball knowing that they are going to have this devastating disease of pulmonary fibrosis in their future.
They have to live with the idea that they have a fatal disease, and, um, they have to get through their teen years and thinking about that. It affects their, you know, uh, trajectory in life. They have to d- to, you know, decide what they're gonna do and how they're gonna handle this and how they're gonna cope with this.
It's very difficult for the families to try to absorb all this. But it's also a research, uh, you know, reality that we know this cohort of people are going to develop pulmonary [00:04:00] fibrosis. Mm-hmm. Therefore, you know, it's not a room of 100 people and you don't know who's gonna develop pulmonary fibrosis in that room.
We can actually see these people growing up to adulthood and follow the disease progression as it's happening and, and as early as we can. So the idea of this breakthrough is just monumental.
Ugo: And Dr. Sanari, your team took that into great consideration and took that approach that centered around the fact that HPS1 patients will with, with a great degree of certainty, 100% get pulmonary fibrosis.
Can you walk us through what you and your team did- Yeah ... um, profiling hundreds of metabolites and cytokines? What, what emerged, and how did CCL22 and choline rise to the top?
Resat: Mm-hmm. Yeah, as, as Donna mentioned, actually, uh, this, uh, situation of HPS, [00:05:00] actually pulmonary fibrosis, especially important scientifically as well because since patients are, uh Eventually developing that makes a kind of predictability with age, and that is very unique, uh, situation because, uh, that can help us identify some of the patients early on even before the, uh, fibrosis or clinical symptoms emerge.
Because in general there are multiple forms of pulmonary fibrosis-
Ugo: Mm-hmm ...
Resat: that, uh, you, uh, and you don't know the cause, but then you, uh, the patient wants the clinic, uh, with the symptoms, they are already, uh, at the late stage. Mm-hmm. So that's why the HPS pulmonary fibrosis research is for bio- ca- uh, biomarker discovery, it's, uh, giving unique opportunity.
So because of that, uh, we, uh, decided the clinical questions whether we can identify some, uh, markers which is, uh, detectable even maybe patients emerge or during the progression, uh, using HPS pulmonary [00:06:00] fibrosis. So, uh, we, we ask critical question whether we can, we can, uh, use HPS-1, uh, patients, uh, with and without pulmonary fibrosis.
Mm-hmm. Because those patients are already e- enrolling the natural history clinical protocol at NIH, uh, even before they develop pulmonary fibrosis. We decided to check the, the na- natural course of the, uh, alterations. So we decided instead of, uh, checking only one marker, we want to integrate all. Mm-hmm.
Uh, so to do so we, uh, check the serum, uh, metabolomics, uh, and also serum, uh, cytokine, chemokine, uh, profiling. Uh, we integrated pulmonary function data and also age. So we, uh, uh, incorporated, uh, and conducted network analysis. And all this, uh, data, uh, show us actually two molecules stand out, which is CCL22 and choline.
[00:07:00] What are these? Uh, CCL22 is a immune, uh, uh, signaling molecule which is, uh, synthesized and released by immune cells- Mm-hmm ... like macrophages, um, and, uh, fibroblast. And, uh, choline is a essential nutrient, but it has critical role in the metabolism, uh, cell membrane structure and, and also one of the critical function is the redox balance, which also involve oxidative stress.
So we found that these two molecules are increased with the, uh, pulmonary fibrosis, but also it associated with the, uh, the, uh, correlation, uh, or declining with the, or worsening with the pulmonary function. And, uh, this, this was actually important. Uh, and, uh, we... Ano- another thing is that these two molecules are help to distinguishing the patients with pulmonary fibrosis, uh, from those of, uh, without pulmonary fibrosis.
Ugo: It, it's really [00:08:00] impressive to me that, and we spoke a little bit before this, that- We have a biomarker now, right? So what does this mean, Donna, to the families of the people that you represent that are living with HPS with a certainty that they're going to get pulmonary fibrosis and to be able... And it's a simple blood test.
It potentially could be a simple blood test. What does that mean to the families?
Donna: Well, first of all, working with Dr. Sanar has been a blessing because not only is he brilliant, but he's also wonderful and, and approachable and, and nice and lovely. So it's been a, a journey that everyone has, uh, really enjoyed and, and loved to work together.
Um, but I think that it brings, um, hope. I think we don't have a treatment for HPS, uh, specifically yet, and I think that these kind of breakthroughs certainly are medicinal. It [00:09:00] gives hope. It makes them feel like, you know, s- there's some light at the end of the tunnel. I also think that, you know, for us it, it's encouraging to know that we might actually be able to do repurposing te- tests and, like, we will be able to see if, you know, know how to handle our family member prior to them developing symptoms.
It lets us change our standard of care so that we actually know when to, you know, how to proceed with how frequent our CAT scans should be, or how much we should concentrate on environments that, that their people are in. It, it actually helps us really handle this disease so much better.
Ugo: The, the way I've, I've interpreted all of that is it's not just a signal for the pulmonary fibrosis itself, but I think from a from a personal perspective, it sounds like it's a signal for hope as well, a [00:10:00] signal for progress.
Um-
Donna: Absolutely.
Ugo: Dr. Cinar, Puerto Rico, I want to talk briefly about Puerto Rico and how important the population in Puerto Rico. Uh, they have a higher prevalence, 1 in 1,800 versus 1 in a million- Mm ... uh, worldwide. How important was it for you and your team to validate this study in Puerto Rico?
Resat: Yeah. In, in general, biomarker discovery's validation is essential.
You should have a independent cohort. So we, uh, our core, uh, studies we, we ca- uh, we actually use the NIH, uh, cohort. Mm. But then since there is a higher prevalence of, uh, HPS, uh, in, in Puerto Rico, we also, uh, collaborate with the clinicians and scientists there. Uh, and we were able to, uh, confirm our findings in the, in the, um, Puerto Rican cohort.
Yeah. So that, that was kind of important for us, uh, because sometimes, uh, in the different locations, uh, uh, with the biomarker discovery, you may find different things. [00:11:00] So that was kind of reassuring because this is a rare disease. We have a low number of, uh, subjects compared to the other common disease.
That was important. But also I want to emphasize, we were, we had also another rare opportunity because I mentioned these patients were, most of them are follow-up with the, uh, uh, natural history protocol we were able to monitor individual patients like at 10 years or five years right before pulmonary fibrosis develop or in the course of the pulmonary fibrosis during their every annual visits.
So we also found that, uh, this, for instance, particularly in CCL22, we found that, uh, fi- with fibrosis, this is increased, but also once the pulmonary function decline, that's further increased. That suggests that it may not only, uh, identify the patient at risk, but also it may allow monitoring the disease progression- Hmm
in the future. So that was [00:12:00] important because for the patients, uh, I mean, right now we have pulmonary function test or CAT scan. These are great, and these are really valuable, but sometimes they don't give a, a in-depth answers what is exactly happening in the lung, and also, uh, you cannot really test regularly, so we need a more, a less, uh, invasive test like blood test, uh, which you can actually routinely do or, or, uh, more regularly do.
So, and also patient needs to know, uh, especially HPS community because they are, uh, developing, uh, this disease, uh, predictably. They, they need to know when the fibrosis is starting. Is it progressing, or am I at risk? Or if there is any treatment, whether this biomarker can track the treatment response, or it can be kind of biomarker-based treatment, this particular patient.
So these are kind of important, uh, uh, points
Ugo: You, you mentioned treatment and it, I, I, I remember it a part of [00:13:00] what you guys on your team worked on was the role of in- of inducible nitric oxide synthase. And can you tell us a little bit about what that is and how it's, it, it plays a part in HPS? Mm-hmm. And what that could mean for potential therapeutic, uh goals and, and targets-
Resat: Yeah
in the
Ugo: future.
Resat: As a, as a kind of translational scientist also, once we find something, we try to understand what does it mean? You know, mechanistically we need to investigate. Uh, so we ask the question, what is the source of this uh, metabolites or what, what it is doing? What is the pathway, uh, which may involve maybe pro- uh, progression.
So that, that's kind of this informations help us also identify maybe therapeutic target. So once we, uh, explore, uh, this, uh, we used a, a single publicly available single, uh, cell RNA transcriptomics data in HPS patients, HPS mouse model, and also IPF. So we found that these [00:14:00] are, uh, expressed in the, in the macrophages and the fibroblasts.
So we go back in the animal model and in the cell cultures, we try check, those cells are really producing and in vitro or ex vivo we were able to generate those with the fibrotic, uh, stimuli. And then, uh, one of our networks analysis suggest that maybe there might be perturbation in the oxidative stress.
Mm-hmm. And then upstream can be iNOS signaling. So we, we try to check, uh, this, whether iNOS inhibition can restore these alterations. So, and fortunately we found that once we inhibit, um, activated cells with the iNOS inhibitor, CCL2, uh, generation and release and also other pro-fibrotic m- uh, modulators are attenuated.
So that suggests that, uh, in this particular conditions, iNOS inhibition, uh, can be potential therapeutic target, especially iNOS and CCL22 can be important, uh, [00:15:00] pathway or therapeutic pathway we can target in the progressive pulmonary fibrosis.
Ugo: I, I mean, the signal, signal for hope, uh, is definitely standing out here.
your paper had a really interesting editorial from Doctors, uh, Gincia and Herzog at Yale, and they wrote the, the editorial that's accompanying the paper, and the claim was really remarkable, that the studying of, uh, essentially rare diseases could have a significant impact on diseases that, uh, affect, uh, a wider population.
Can we talk a little bit about that and, uh, give us your, your thoughts and insights on what that could mean for the fi- pulmonary fibrosis world at large, and, uh, and what kind of impact that you're, you're looking forward to?
Resat: Mm-hmm. So yeah, that, that was actually very uh, nice, uh, editorial for our paper, uh, capturing the critical point.
So this is one of the exciting findings in our paper, that our findings, although we focus on the Hermanski-Pudlak syndrome pulmonary [00:16:00] fibrosis, the implication or the findings can be beyond, uh, rare disease. So that also show that, uh, we can learn from the rare disease broadly, and it can, it can, uh, uh, be important for the, uh, pulmonary fibrosis in, in a general community.
So as I mentioned, the CCL22, is ex- the, like, the signature is similar with the HPS pulmonary fibrosis and also, uh, IPF pulmonary fibrosis. So that suggests this could be a, a broader, and even we use animal model, which is, uh, generally for, uh, IPF as well. So INOS inhibition was also, uh, therapeutic.
So the, this is, uh, this is a, a really, uh, important, uh, finding, uh, to generalize. But I, I also want to emphasize, um, that we have to be cautious because these biomarkers are not readily available-
Ugo: Right ...
Resat: as a blood test commonly, uh, for all, uh, forms of pulmonary fibrosis. But I think in our next steps [00:17:00] we have to maybe, uh, consider exploring this broadly for other ILDs, other progressive ILDs, so that could be also meaningful-
Ugo: Wonderful
Resat: on this study.
Ugo: Um, I know, uh, Donna has been a strong advocate for more investment into, um, rare diseases and, um, especially understanding how this can have the broader impact, um, for, for the IPF and pulmonary fibrosis, uh, communities at large. Thank you all so much.
So here's what I want you to sit with after this conversation.
We just heard about a rare disease, one that most of us will never see in clinic, that is teaching us something fundamental about how fibrosis works. Choline and CCL22 aren't just biomarkers for fourteen hundred patients with HPS. They may be signposts for a mechanism that operates across the entire spectrum of progressive pulmonary fibrosis.
That's the [00:18:00] power of studying rare diseases with rigor and intention. But I also want you to remember the other side of this story. Donna Appel has been doing this work for, for decades, building a network, connecting patients to researchers, making sure that a community that could easily be overlooked stays visible.
The validation cohort in this study came from Puerto Rico, where HPS affects a population that doesn't always have a seat at the table in biomedical research. That matters. Who we study and who we include shapes what we find. And then there's the science itself. Dr. Cinar's team didn't just find biomarkers, they found a potential therapeutic lever in iNOS.
That's the kind of discovery that moves from the bench to the bedside, not tomorrow, but the trajectory is real. So whether you're a researcher, a clinician, a patient, or a family member, the takeaway is the same. Rare diseases aren't footnotes. They're the front door to [00:19:00] understanding the diseases that affect millions.
And the people living with them aren't just waiting for science to catch up. They're driving it. That's it for this episode of ATS Breathe Easy. Looking forward to seeing you guys on the next one.