There are several opportunities coming up in the very near future, in the US, Canada, and Europe (and possibly other countries) for mRNA therapies for PCD.
We are planning a town hall this month to discuss what is on the horizon, what the community needs to do to facilitate these studies, and what we can expect in the near future.
To begin with, researcher and study sponsors need to determine what outcomes/endpoints will satisfy regulatory agencies in various regions. To get a drug approved, it is not enough to show that it is safe. You also need to show that it makes a meaningful change in the disease in question. PCD is challenging, since there is no identifiable pattern to FEV1 (a major endpoint), exacerbations, or imaging in PCD patient, unlike in other respiratory diseases. So we are going to have to get creative. Fortunately, some very smart people from around the world are working on this right now.
What does this mean for the PCD community:
1. We have to do a pre-study or studies in preparation for the mRNA studies. These are studies that will demonstrate it is possible to find endpoints that are actually measurable in PCD. Endpoints are the data elements that demonstrate improvement from a therapy or intervention. Examples are mucociliary clearance, imaging, spirometry, etc. These pre-studies will assess which endpoints are the most reliable for therapeutic trials. The first of these pre-studies, which may be referred to as natural history studies (not to be confused with the long-term natural history collected in a registry) need to be done in adults, since the first mRNA therapy trials will start with adults for safety reasons.
2. In the very near future, adults with PCD will be asked to participate in studies as described above. This may require travel and it may require the sacrifice of personal time, but we REALLY, REALLY need to do this. We are in danger of losing interest from mRNA companies if we cannot recruit enough patients for studies and that would be a tragedy for all of us.
This is a tough thing for our community. There are not enough PCD people in any one area to do studies–there are not a lot of us at all–so we have to go to extra lengths to participate in trials. When travel is required, costs for participation will be covered, but time off of school or work can also be challenging. Sometimes, despite strong desire to participate, it just is not feasible to be in a study and we totally understand that. If you have the ability to participate at all, though, this is the time to get involved. No one else but PCD patients can get research answers for PCD, so it is ultimately up to us.
More information about this study will be available soon.
3. mRNA therapy does not alter the genome, contrary to some of the misinformation currently coursing through our culture. Rather, it is a way to correct the the transcription process so that the flawed genetic messaging from PCD-causing genetic variants that result in the production of faulty ciliary proteins is over-ridden. It doesn’t change the gene–just tells it to do something else. If the therapy works (so far it has not been tried in humans, so there is always a chance it won’t work), the message is corrected, the right protein is produced and function is restored. This is the goal and only well-designed studies will show us if it actually will work in PCD.
As currently envisioned, mRNA therapy will be gene-specific, so knowing your genetic info will be critical. Because of this, there are efforts underway globally to make genetic testing more accessible and affordable for the entire community. Additionally, there is a lot of effort going into variant identification and clarification for people who have one known pathogenic hit, but the second has yet to be discovered or for people who have PCD confirmed by biopsy or high-speed videomicroscopy, but no known genes yet. More on these programs to come soon, as well.
PCD researchers are also ramping up efforts to make sure genetic panels include all known genes and to address potential novel variants and unique modes of inheritance that are not incorporated into current panels. We will be having an upcoming town hall to discuss PCD genetics and genetic challenges with Dr. Will Hannah and Dr. Ben Gaston, as well–look for an announcement soon.
mRNA therapy has the potential to be the real deal–a therapy that actually works on the underlying problem and restores ciliary function. We have a big job ahead of us–get people into natural history studies quickly so we can have the answers that will allow us to move into therapeutic trials asap!
There several companies looking at mRNA therapy for PCD, including Ethris and ReCode. It’s definitely worth a look at their websites to see what their PCD programs look like. It has taken a while to get here, but things are now moving very rapidly, so let’s get ready!
Why do challenging lung infections occur in PCD?
Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder that affects the cilia, which are tiny, hair-like structures that line the respiratory tract and other parts of the body. These cilia play a crucial role in moving mucus and other substances out of the airways. When ciliary function is impaired due to PCD, it can lead to chronic respiratory issues and an increased susceptibility to lung infections.
What factors contribute to challenging lung infections in PCD?
Impaired Mucus Clearance: The ciliary dysfunction in PCD results in ineffective clearance of mucus from the airways. This creates an environment where bacteria and other pathogens can thrive, leading to recurrent respiratory infections.
Chronic Inflammation: The continuous presence of mucus and the inability to clear it properly can cause chronic inflammation in the airways. This inflammation further impairs lung function and increases the likelihood of infections.
Structural Abnormalities: PCD can also lead to structural abnormalities in the airways, such as bronchiectasis. These changes make it difficult for the lungs to effectively clear infections, as pockets of mucus may become trapped in dilated airways.
Laterality Defects: About half of people with PCD will have a ‘laterality defect,’ meaning their organs are not in the typical arrangement or did not develop correctly. When splenic function is affected by laterality defects (a rare occurrence) the ability to fight infection may be impaired.
Delayed Diagnosis: PCD is often underdiagnosed or misdiagnosed, leading to delayed initiation of appropriate treatments. This delay can contribute to the development of more severe lung infections.
Frequent Antibiotic Use: Due to recurrent infections, individuals with PCD may need frequent courses of antibiotics. Prolonged or repeated use of antibiotics can lead to the development of antibiotic-resistant strains of bacteria, making infections more challenging to treat.
How are challenging lung infections managed in PCD?
Management of challenging lung infections in PCD involves a multidisciplinary approach, including:
Antibiotics: Depending on the type of infection, antibiotics may be prescribed to treat bacterial infections. It’s important to choose antibiotics carefully to avoid the development of resistance.
Airway Clearance Techniques: Physiotherapy and airway clearance techniques are crucial in helping individuals with PCD clear mucus from their airways. These may include chest physiotherapy, postural drainage, and the use of positive expiratory pressure devices, etc.
Inhaled Medications: Bronchodilators and inhaled corticosteroids may be used to manage airway inflammation and improve lung function.
Preventive Measures: Vaccinations, including influenza and pneumonia vaccines, are important to help prevent respiratory infections. Regular monitoring by a healthcare team familiar with PCD is essential for adjusting treatment plans based on the individual’s specific needs. Early and proactive management can help minimize the impact of challenging lung infections in individuals with PCD.
National Patient Experience Week April 29, 2024- May 3rd, 2024.
We are proud to partner with ReCode Therapeutics on a video project, shedding light on the patient experience through the patient lens.
PART 1: Shedding light on PCD- Introduction
Patient Experience Week honors the profound daily impact healthcare professionals have on the patient experience. As this year’s commemoration begins, we’re proud to introduce you to Bill Anton, Chairman of the PCD Foundation and a patient advocate living with Primary Ciliary Dyskinesia (PCD). Earlier this month, we spent a couple days with Billy learning about the day-to-day management of his PCD, his current symptoms and treatments, and his future outlook.
At ReCode, we are committed to transforming the treatment landscape for genetic diseases like PCD. Through our research, including our PCD-focused mRNA-based therapy, RCT1100, designed to restore ciliary function by targeting the disease’s root cause.
PART 2: Compliance and Illness
Everyday, Bill Anton, PCD Patient and Chairman of the PCD Foundation, asks himself, “What am I doing today to give myself the best chance at tomorrow?”
As Patient Experience Week continues, and every week at ReCode, we’re focused on the unique challenges Primary Ciliary Dyskinesia (PCD) presents, including chronic respiratory infections and the constant need for vigilance in health management. Despite these challenges, patients like Billy and their families face each day with hope and determination.
We share in their optimism. Stay tuned for the full video.
PART 3: Treatments
This Patient Experience Week, let’s reflect on the critical need for tailored treatments in healthcare. In today’s video excerpt, Bill Anton, PCD Patient and Chairman of the PCD Foundation, discusses the lack of specific therapies targeting Primary Ciliary Dyskinesia (PCD). At ReCode Therapeutics, we aim to change this deficiency with RCT1100, our pioneering mRNA-based therapy targeting the genetic roots of PCD—specifically mutations in the DNAI1 gene.
Part 4: Hope for the future
As Patient Experience Week draws to a close, we extend our deepest gratitude to the PCD Foundation and Bill Anton for their partnership and collaboration. Working closely with those who live with PCD inspires and propels our work forward.
Researchers and patients should not be disconnected. Our collaboration can bring about a future that, in Billy’s words, “would not be believable that it would happen this soon.” Ongoing advocacy from patient communities helps advance research, and this symbiosis makes for a promising future guided by collaborative and rigorous science.
PCD diagnosis continues to be challenging. All current testing options available to aid in PCD diagnosis (biopsy with TEM, nasal nitric oxide measurement, high-speed videomicroscopy, immunofluorescent assay of ciliary proteins) have limitations and do not work in all cases of PCD. Genetic testing is getting better all the time, but it is not widely available in all areas and, even where it is available, it can be difficult to get insurance coverage for it. Also, we have not yet identified all the genes associated with PCD, so while the gene testing panels are far more comprehensive now than in the past, they still are incomplete. A PCD genetic test can positively make the diagnosis if known mutations are found. But a negative PCD genetic test does not rule out PCD. It just rules out PCD caused by genes/mutations evaluated on the specific panel.
Some patients who most likely have PCD fall through the diagnostic cracks because the technology for diagnosing the disorder has not yet caught up to their specific form of PCD. But sometimes people who have all the symptoms of PCD may not actually have PCD. This is the potential danger with a ‘clinical-only’ diagnosis of PCD, based on symptoms alone. Getting a diagnosis can be reassuring and can help direct treatment plans for families. However, having all the symptoms of PCD does not constitute a confirmed diagnosis (for the reasons below), and relying too much on a clinical diagnosis of PCD could mean that the real underlying disorder goes undetected and untreated.
Since no test can pick up all cases of PCD, there is also no way to definitively rule PCD out. This means a fair percentage of families (US) remain in limbo regarding their diagnosis. Often, in the absence of confirmatory testing, we hear that the diagnosis of PCD was made because ‘all the symptoms fit, everything else was negative,’ so the family is told ‘it must be’ PCD.’’ Given the difficulty confirming the diagnosis, this is understandable and while this sometimes turns out to be correct and the diagnosis of PCD is ultimately confirmed, there have also been many cases in our community where diagnosis based on symptoms alone has ultimately proven to be wrong and what ‘must be’ PCD turned out to be something else entirely.
Here are a couple of things to consider:
First, PCD is not a diagnosis of exclusion. A diagnosis of exclusion is one that is made on the basis of ruling out (excluding) everything else, so that what remains ‘must’ be the diagnosis. PCD should not be treated like a ‘default’ diagnosis, even if all the symptoms fit. This is because:
Second, PCD is a genetic disorder, not simply a pattern of symptoms. It is caused by mutations/variants on specific genes* that produce proteins important for the structure and function of cilia. A pattern of symptoms may suggest that the genetic disorder PCD should be considered, but if PCD genes are not affected, then it is not PCD, regardless of whether the symptoms are similar or not. Since we do not know all the genes yet and cannot test for them all, other forms of PCD testing are focused at looking for secondary evidence of the primary (genetic) defect. For instance, if you have PCD-causing mutations on DNAH5, the consequence of these mutations is loss/shortening of the outer dynein arms, and the evidence for this can be seen by examining a ciliary ultrastructural biopsy. A pattern of outer dynein arm loss on biopsy that is consistent with PCD serves as a ‘genetic proxy’ providing evidence that there is, indeed, a PCD genetic defect, whether that defect can yet be detected by genetic testing. Of course, the biopsy cannot tell you for sure that DNAH5 is the gene involved. It just provides evidence that a gene important in the production of an outer dynein arm is involved, and this provides reasonable confirmation of the genetic ‘primary’ diagnosis. The same is true for other forms of testing for PCD, which attempt to use secondary evidence–the consequences of the primary (genetic) defect–to confirm that the genetic defects required for a diagnosis of PCD exist. These tests include nasal nitric oxide (nNO) measurement, ciliary beat analysis by high-speed videomicroscopy or tagging proteins with fluorescent dye. All of them attempt to establish that there is a PCD genetic defect by measuring or otherwise evaluating the consequences of that defect.
Cystic fibrosis (CF) is also a genetic disorder caused when mutations on a specific gene affect the function of mucus production and excretion. These mutations result in a pattern of symptoms commonly seen in CF. This pattern of symptoms might lead a physician to pursue diagnostic testing for CF. But in contrast to PCD, it is extremely uncommon for the diagnosis cystic fibrosis to be made on the basis of symptoms alone. Physicians are extremely reluctant to tell a family facing a possible diagnosis of CF that their child has a lifelong genetic disorder for which no cure exists without making absolutely sure they have reliable laboratory tests or other verifiable evidence–not just symptoms–to support the diagnosis. Yet this happens all the time with PCD–at least in the US at centers less familiar with the disorder.
The willingness to diagnose PCD when there is no laboratory confirmation is partly a reflection on how challenging PCD diagnosis is, but it is also partly a reflection on what can be interpreted as a somewhat dismissive attitude about the importance of getting the diagnosis right in PCD and other non-CF causes of bronchiectasis when compared to CF. This can be a very big problem–especially with pulmonologists unfamiliar with CF and PCD. It happens in both pediatric and adult settings, but we hear about it more often on the adult side, where it is common to lump patients into either CF-bronchiectasis or non-CF bronchiectasis categories and to focus less on underlying causes for non-CF bronchiectasis then on just treating the bronchiectasis. This may be understandable, but it is not helpful for patients who carry a misdiagnosis of PCD or who need to have their PCD diagnosis confirmed. Nor is it helpful for the PCD community as a whole, as we seek to better understand this disease. PCD, like CF, is a genetic disorder with lifelong health implications and family planning implications. PCD may also be associated with other issues that will not be a factor for people who do not have ciliary gene defects, like situs anomalies, in/subfertility, congenital heart defects and an increased incidence of connective tissue problems like chest wall deformities and scoliosis. It is completely reasonable for patients to want to know for sure that they have PCD–or do not have PCD–so they can plan their future armed with accurate information. It is also important for the patient community that every effort is made to get the diagnosis right, as we are hopeful that we will find therapies and cures based on addressing the underlying genetic defects in PCD.
A number of other disorders result in similar–sometimes nearly identical—symptoms to PCD. Some of them have effective treatments which will be missed if the diagnosis of PCD is given incorrectly and the search for the real underlying problem stops. For instance, rare immunodeficiencies–of the sort not included in typical immune system dysfunction work ups–have recently been found to be the cause of symptoms in people who thought they had PCD. Some of these people believed they had PCD for decades. In many cases, these individuals may have benefited from bone marrow transplant and/or immunotherapy. Instead, because they were diagnosed and treated as PCD, which currently has no specific therapy, their lungs became very damaged and they required transplant. It was during the transplant eval that their actual diagnosis was discovered. In some cases, the outcome of missing a diagnosis of immunodeficiency (and it is reasonable to assume this would be true of other misdiagnosed underlying disorders) and labeling it PCD resulted in very bad–and even fatal–outcomes for the patient, which could possibly have been avoided if the correct diagnosis was made and correct treatments were started. So getting the diagnosis right is not a small matter and it should be taken seriously. The overlap between–and consequent misdiagnosis of–PCD and a very rare immunodeficiency caused by mutations on the RAG1 gene has been seen enough times now that one commercial PCD genetic testing panel in US recently included this gene so RAG1 immunodeficiency can be evaluated at the same time as PCD.
Issues with misdiagnosis of PCD are serious and ongoing. We are still in the discovery phase with regard to both PCD genes and how PCD gene defects translate into the disorder, making these issues even more challenging. This is in large part the reason that multi-national research networks have been set up in Europe and in the US. Expertise for making the diagnosis exists and experts in these international networks are happy to assist community physicians with difficult cases. Sometimes there just won’t be an answer right now. This is tremendously difficult on families and on health care professionals and every effort should be made to provide answers as testing options improve and to not just assume ‘it must be PCD.’ When the diagnosis of PCD cannot be confirmed, PCD Clinical Centers use the designations of ‘probable’ or ‘possible’ to clarify the status with regard to PCD diagnosis. These designations recognize that it is simply not possible to confirm all cases of PCD right now and allow for aggressive treatment of the underlying condition, while still acknowledging that additional confirmatory PCD testing or consideration of non-PCD causes may be required in the future.
We have put extraordinary effort into building an expert network in North America to improve patient access to experts who can avail themselves of all testing options, understand the ever-evolving genetics of PCD and who commit themselves to being involved in research to improve diagnosis and treatment. These professionals are without peer when it comes to diagnosing and understanding PCD and they are happy to be a resource for families and for health professionals. We encourage everyone to take advantage of it.
