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Welcome to UAB MedCast, a continuing education podcast for medical professionals. Providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole (Host): People with primary ciliary dyskinesia may have persistent or recurrent infections, which can significantly disrupt their quality of life and sometimes lead to permanent damage. And life-threatening complications.

Welcome to UAB MedCast. I'm Melanie Cole. Joining me is Dr. George Solomon, Assistant Professor in the Division of Pulmonary Allergy and Critical Care Medicine at UAB Medicine. Dr. Solomon, welcome back. You're always such a good guest. So we're talking today about primary ciliary dyskinesia. What had been the thought previously regarding PCD? We did a previous podcast on this topic. What has changed? Do you have any exciting updates to share?

Dr George Solomon: Yes, we do. Quite a few, Melanie. I think the field is evolving. It's not evolving by leaps and bounds, but evolving in a slow pace with a lot of improved understanding of the illness in both the clinical presentation of the illness, but also some of the science behind it. So we'll talk about that a good bit today and I'll highlight a couple of things that I want to discuss as themes regarding the progress of the condition overall, the scientific explanation.

So the first of those is, and just to remind our viewers from the previous podcast, this condition is a genetic condition much like cystic fibrosis, which some may be more familiar with. However, unlike cystic fibrosis, which is a monogenetic disease, which means that one mutation in one gene in our genome is affected causing the illness. This condition is caused by mutations in at least 50 known genes. Now, when we last spoke, that list of known genes that could be affected causing primary ciliary dyskinesia was probably in the low 30s. We now know there's evidence of at least 50 genes involved with the structure and function and regulation of the cilia, which is our hair-like projection, which helps to move mucus in several of our organ systems, but primarily in the sinopulmonary tract, so the sinuses, upper airways and lower airways in the lungs. At least 50 genes are known to have mutations, which can cause this primary ciliary dyskinesia. And that brings up an automatic question. When you have 50 different genes, which can cause a similar syndrome, is the effect in each of those genes exactly the same? In other words, will patients with, for instance, a mutation in a structural protein, the most common of which as an example is the gene called the DNAH5 mutation or gene, will effects of that gene cause the same type of condition as effects in a gene that causes regulation or other functions of the cilia itself?

And the answer we're learning more and more in the last few years, since we last spoke of this topic is no, that will not cause the same type of condition. Mutations in many of these genes across a spectrum can cause a similar what we call clinical phenotype, which you outlined earlier the highlights of it. One is significant sinus and pulmonary infections, which can progress throughout the lifetime, really due to impairment of the clearance of mucus. But the severity of that phenotype, in other words, how much that happens, to what extent it causes damage in the airways and to what extent other organs in the body are affected, which include the kidneys, reproductive tract, to some extent the heart and the abdominal organs, the extent of which that phenotype manifests is due to the severity of the gene implicated and also the severity of the mutation type. And we weren't so sure about that a few years ago, but now we know that likely that is the case. And that's because of some new publications which have been released. One came from large database of patients in Europe, which has been working on this for quite some time. They have cataloged thousands of patients in Europe with primary ciliary dyskinesia, and have done some analysis looking at what is the severity of phenotype based on lung function, based on severity of infections, based on age at which the patient develops complications, an important of one those is the development of bronchiectasis, which means that the patient has permanent airway damage due to the primary ciliary dyskinesia. And that appears to coassort with different mutations in different genes, which are implicated in the condition.

Now, I won't have time to go into more details on that today, but suffice it to say that that tells us that it's important to understand the genotype-phenotype correlation. And what that means is understanding the severity of the genotype, which is the mutation, and in what gene the patient has and how that links to how their phenotype may be, because that tells us a bunch of things. One is it helps us with prognosis, how this condition may play out for each individual patient. The second is it tells us a lot about future treatment. And the reason I tell that is because this is the other major development that we're seeing, is the field of pulmonary medicine is beginning to get more sophisticated with the development of genetic-based therapies.

Genetic-based therapies really tell us a way to correct the gene defect rather than having to treat a symptom of the gene defect. So an example of a symptomatic treatment for a genetic condition, like primary ciliary dyskinesia, might be take a drug that makes the mucus easier to move out. And while that's a very viable strategy, and we'll talk a bit more in a few moments about strategies that are being looked at. But for in the meantime, if you can correct the gene itself, that's correcting the basic problem with the condition, so understanding these types of genetic correlations we've been talking about for the last few minutes is a way to both prioritize and better understand the way that the gene has to be corrected, to know how we're going to improve the condition.

Melanie Cole (Host): That's fascinating. And as you're telling us about these updates and these changes, please do go into those strategies and how this research and these updates are translating to better patient care.

Dr George Solomon: Right. So first strategy that we should talk about is the symptomatic strategy I mentioned earlier. So we're not going to be able to solve delivery and/or repair of every gene defect in primary ciliary dyskinesia quickly, that's going to take years, which means that patients need treatments that can help to stabilize their illness and treat their symptoms in the meantime. So there are actually a lot of efforts being made in the PCD community to look at that.

The first of those is we're looking at, and this may sound like a simple thing, but it's actually not, we are looking as a group, the US Primary Ciliary Dyskinesia Foundation, as well as the European Consortium of Primary Ciliary Dyskinesia Centers, both are working in parallel to develop optimized guidelines for therapy. There has been a guideline document released a few years ago, but it made very few recommendations. So that will need update in the coming years. In addition, we need to develop clinical research strategies for this condition. So development of both a patient database that patients can be identified as potential research subjects with a well-established diagnosis and also better standardized care for these patients will help us to prime that group for research efforts.

One such research effort, which is going actually through a phase III study, is a drug that actually treats the ion channel called the epithelial sodium channel, which is oftentimes abbreviated as ENaC. ENaC has been implicated as having defective function or overly effective function, I should say, in the conditions like primary ciliary dyskinesia and also cystic fibrosis and other conditions like that. And when this protein malfunctions it results in a change in a mucus that makes it more difficult for it to relieve itself and be removed from the lungs. So if the mucus can't remove itself from the lungs, it's going to impair the clearance of infections and irritants that come in from our environment, those things are what damage the lungs really and drive the chronic inflammation in the lungs, which causes many of the problems that people with conditions like PCD have. And so we can hopefully help to overcome some of that limitation by offering treatments, which move that forward. And so one such study is moving forward to what we call a phase III, which is a study that would help with labeling or seeking FDA approval for the drug. And this is a drug which actually inhibits, which means it blocks the function of that ENaC channel. And by doing that, it helps to make the mucus more effectively cleared out of the lungs and we think will improve lung function, reduce exacerbations or flares of the condition oftentimes due to infections and will help with overall symptoms in the lungs and sinuses with these patients. So we're anxiously anticipating the start of that study. There was a successful pre-phase III study called a phase II study conducted recently. That study did help us to understand that this drug was very safe and had early trends towards efficacy in the domains we just outlined, including the lung function and reduction of pulmonary exacerbations or pulmonary infections. So we're eagerly anticipating the start of that study. And our site will be enrolling patients here along with sites across the US and these consortia we just talk about.

In addition, since we last talked, there has been a couple of larger studies conducted in Europe, which showed that antibiotics, especially in the class of antibiotics called macrolide antibiotics and those that are less familiar with those may recognize like azithromycin, for instance, as one of those antibiotics, has been shown to help modulate the immune system, especially in patients that have pseudomonas infection, which is a chronic infection that many patients with PCD will acquire over time. And so those patients may benefit from taking this therapy on a recurrent basis to help modulate their immune system and modulate the way the body responds to infections and help to prevent decline of lung function and worsening pulmonary disease. Those we would call symptomatic treatments, which have moved us forward.

In addition, we're moving forward with, as I mentioned, standardization of care for these patients. And that allows us to have a set of patients who are treated similarly and with the best expert opinion on care at this point. So when they come into a clinical trial, we can know that the drug that's being given to them is really affecting them and making a positive endpoint on them, if positive, rather than it being subtle tweaks in their other management of their care. So this helps us to standardize the patients in our trials and also helps them to get the best and most accurate answer on what might be effective for them in the future.

Now, as I outlined earlier, the next thing we're trying to do is really understand the science of mucus, understand the science of the cilia genes and how they function, so we can really move towards correcting the basic defect in primary ciliary dyskinesia, which really comes down to that defect in the genes, which cause defects in the cilia function or structure or all the above.

And as a result, we think that in coming years, we will be able to advance therapies that either deliver, repair or edit and repair the gene defect underlying many of the especially common causes of primary ciliary dyskinesia, and that's really work that's come out of these studies we've been outlining during this discussion.

Melanie Cole (Host): Wow. That's so much information, Dr. Solomon. As we wrap up and you're speaking about ongoing care for the families and patients, you're speaking to other providers, now what would you like them to know about those clinical trials, the research being done and the communication with the referring physicians when it comes to PCD?

Dr George Solomon: That's a great question, Melanie. I think that the key here is this is a rare condition, which is challenging to care for. It's challenging to care for the patients because they have complex illness, which affects almost every domain of their life. So I think the key here is please refer those patients to our centers so we can assure accurate diagnosis and provide them access via our clinical research network to these trials that this patient so choose to be involved with them, so they can optimize their care early and most effectively as new therapies come about.

Melanie Cole (Host): Well, that's so interesting. And as those new therapies come about, I certainly hope that you will come back and keep us updated because you are just a wealth of information. And thank you again for joining us.

A physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST or by visiting our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.