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On June 18th, Cystic Fibrosis Canada hosted the second annual virtual Community Forum, themed, “Spotlight on CF Research”. In case you missed the webinar, we’re recapping what was discussed and sharing the Q&As from our stellar lineup of Canadian cystic fibrosis researchers.
[Timestamp for video 9:20-22:35] Dr. Adele Coriati, PhD– Focused on cystic fibrosis related diabetes research
Cystic Fibrosis Related Diabetes (CFRD) affects nearly one in three people with CF and can cause rapid health declines. Earlier detection could lead to earlier care and better outcomes. Dr. Coriati, assistant professor in the Department of Nutrition at the Université de Montréal detailed her study that is investigating whether certain fat molecules in the body (lipids) can help detect cystic fibrosis-related diabetes before symptoms appear.
How can cystic fibrosis be linked to diabetes?
Dr. Coriati: CF mainly affects the lungs and digestive system, but it can also affect the pancreas, the organ that helps control blood sugar. Over time, the thick mucus from CF can damage the pancreas, making it harder for it to produce insulin. Insulin is the hormone that keeps blood sugar levels normal. When the pancreas doesn’t make enough insulin, it can lead to a form of diabetes called CFRD. So, even though CF and diabetes are different conditions, the damage CF causes to the pancreas is what links the two. I hope that answers your question.
In children how can cystic fibrosis be linked to diabetes?
Dr. Coriati: The answer for children is the same as the answer to your previous question for adults. Children with CF are less likely to have diabetes when they’re young, but changes in the body can start early. In many children, the pancreas already starts making less insulin at a young age, even if they don’t feel any different. Then, as they grow older, the body also becomes less efficient at using insulin — something we call insulin resistance. That’s why CFRD is usually diagnosed in teenagers or young adults, even though the problems can start quietly in childhood. I hope this answers your question.
In the table, for the post-modulator period, is the percent showed for overweight relate to the general population (population average), or is it a higher number, potentially because of the modulators?
Dr. Coriati: Indeed, the percent shown in the table, i.e. 43,5% of overweight people in the post-modulator period, is the one seen in our Montreal CF cohort, and not the one for the general population.
In the general Canadian population, it is estimated that about 30 to 35% of adults are overweight. So, the number observed in the CF cohort here seems a bit higher. We believe that with the CFTR modulators, because they improve a lot the nutritional status and the digestive function, certain people could gain more weight.
It is not necessarily negative. In fact, for the longest time, the goal in the CF population was to gain weight. Now that we have reached (or exceed) this goal in many individuals, we are facing new challenges, like the risk of diabetes or other metabolic complications. And, this is exactly what our project is trying to explore with the lipid profiles!
Would early intervention begin in childhood? adolescence? or early adulthood? What does the term early intervention mean to your study?
Dr. Coriati: When we say early intervention in our study, we’re mainly talking about catching signs of CF-related diabetes before it’s fully developed, during the stage where the body starts having trouble with blood sugar but hasn’t reached the point of a diagnosis yet. That could be in late adolescence or early adulthood, depending on the person.
So, for us, early intervention means identifying people who are at risk and acting sooner, through things like more frequent monitoring, dietary or exercise guidance, or adjusting care to help prevent the diabetes from progressing.
That said, in the future, if our research shows that lipid changes happen even earlier, we might be able to shift that window to childhood or early adolescence, but for now, we’re focusing on that earlier adult stage where changes first start to appear.
You mentioned that some interventions based on physical activity and nutrition would be good against CF-related diabetes. For patients with insulin-dependent diabetes, would insulin play a role in the lipid control, or not at all?
Dr. Coriati: Yes, you’re right. Insulin plays an important role in the control of lipids. In a healthy person, insulin’s role extend beyond regulating glycemia (the sugar in the blood), it also helps to manage how the body uses and stores fat. For example, it slows down the excessive release of fat in the blood and it helps lipid storage in the tissues when necessary. In CF people with diabetes, this mechanism can be compromised. When there’s a lack of insulin, not only the glycemia increases, but the lipid metabolism also becomes unbalanced. This is why in insulin-dependent patients, insulin can indirectly help the lipid profile.
So, in our project, this is exactly what we study, these interactions, how the lipids change depending on the glucose tolerance level, and also how they could react to interventions like insulin, nutrition or exercise.
Would a 13-year-old child with CF who uses Trikafta can be part of your study?
Dr. Coriati: In our current study, the participants must be 18 year old and over. So a CF child who uses Trikafta could not participate to this specific study.
However, your question is very relevant because the effects of modulators, like Trikafta, are seen very early. And we know that metabolic changes, including weigh change, lipids and even maybe the risk of diabetes, can already be observed in teenagers.
That’s why, in the future, we would really like to expand our research to include young people like this particular patient. Understanding what is happening from teenage years could allow us to prevent CF-related diabetes even earlier.
[Timestamp 25:25- 47:25] Dr. Dao Nguyen, MD, MSc, FRCPC-Shared research on chronic bacterial infections in people with cystic fibrosis
Bacteria can be dangerous for people with CF as their thick, sticky mucus makes it harder to clear, often turning into chronic infections and potentially leading to lung damage. Dr. Dao Nguyen at McGill University Health Centre is researching why in this era of new treatments, are people with cystic fibrosis still plagued by chronic bacterial infections, and how to eradicate the most common bacteria.
Q: I understand your study if looking at those with chronic infections that have pseudomonas prior to starting Trikafta. Is this a population that is declining (e.g., do individuals who start Trikafta prior to culturing pseudomonas have a lower rate of chronic infection)?
Dr. Nguyen: The study that we are doing is indeed focused on those with chronic Pseudomonas prior to Trikafta, and this population is indeed declining, and hopefully will continue to do so. However, our recent work was done for new Pseudomonas infection, and the use of the antibody would also help eradicate those new infections.
Q: Does Trikafta prevent pseudomonas colonization, if one is not already colonized?
Dr. Nguyen: Yes, Trikafta does reduce the risk of Pseudomonas new infection and colonization.
Q: When using the antibody, did you see any differences in regard to treatment sensitivity depending on the strain’s chronicity?
Dr. Nguyen: The effect of the antibody can vary depending on certain features of the bacteria, but it seems to still be effective against strains responsible for chronic infections. That being said, we did not yet test a wide variety of strains.
[Timestamp 54:40-1:19:57] Dr. Larry Lands, MD, PhD- Deep dived into gene therapy advancements
Cystic fibrosis is a genetic disease caused by inheriting two defective genes - one from each parent. Dr. Larry Lands at McGill University Health Centre and Chair of Cystic Fibrosis Canada’s Research Advisory Council is researching a form of gene therapy called prime editing which could potentially correct one or both of these defective CF-causing genes. Dr. Lands’ research could possibly lessen or alleviate the symptoms of cystic fibrosis and holds great potential for treating both the most common CF genes and the rarest. “Once we have a system that is working...we can rapidly move on to other mutations and really leave no one behind,” said Dr. Lands.
Q: Is there a projected/hypothesised timeline for Dr. Larry Lands and his team to arrive at human trials in the development of a potential cure through Cas9/gene-editing?
Dr. Lands: The project is funded for 3 years. By that time, even with the budgetary restraints, we plan to have developed the prime editing mRNA and lipid nanoparticles and then tested this in mice. For human trials FDA (typically we would go through FDA) will want evidence of long term eg 6 months of safety and effect, which will extend beyond the 3 year time line. Then, it will depend upon whether FDA would require studies in non-human primates before going to a human trial. If non-human primate studies are required, this would conservatively add a year. The trials in humans typically start with Phase 1 which is safety in people without CF. These will be followed by further studies of dose, efficacy in people with CF, etc.
Q: I understand there is another team at UCLA in the US working on something similar (see here). Do these teams collaborate? Or are they in pursuit of different genetic editing solutions?
Dr. Lands: There are some resemblances and notable differences that I believe are in our favour. We both will use lipid nanoparticles, but we are developing both inhaled and intravenous lipid nanoparticles while they are doing only inhaled. It is unclear which route will be best to treat as much of the lung as possible, and so both deserve investigation. As an aside, I work with a small biotech that has an inhaled dry-powder mucolytic that our early results suggest would enhance inhaled lipid nanoparticle delivery. This is being explored further.
Many different lipid nanoparticle formulations are possible. We are constantly scouring the literature for the latest developments in the lipid components to continuously improve on delivery.
We also will target the stem cells of the lungs, known as basal cells for a long-lasting effect. The airway cells turnover, with the basal cells being responsible for replenishment. In our lipid nanoparticle development, we are exploring several strategies to functionalize the lipid nanoparticles to target the basal cells.
It is unclear which gene editing system UCLA is using, but their news posts suggest it is CRISPR. We are using Prime Editing which is the latest evolution of gene editing that builds upon CRISPR. Prime Editing uses newer versions of CRISPR that are more efficient and couples it with the reverse transcriptase (RT) enzyme to copy in the correct message, rather than relying on the cell DNA repair process to put in the correction. The advantages of Prime Editing are that: it only cuts 1 of the 2 DNA strands (cutting both strands can set off alarms in the cell that can counteract what is being attempted), it does not rely on cell repair mechanisms, it is much more precise in where it makes the cut so less cuts and insertions in the wrong place that can cause other cellular problems, is more efficient in terms of the amount of DNA corrected and flexible as to where it can make the correction than CRISPR, so that it can be applied to many CFTR mutations. The disadvantage is that the RNA for Prime Editing is much larger than CRISPR and this is where lipid nanoparticle come in as a delivery vehicle that can carry this large a RNA. Our team includes Jacques P Tremblay the leading Canadian expert on Prime Editing. He has been at the forefront of developing the Prime Editing enzymes and developing the guides (ePEGs) to maximize their efficiencies. So, I am optimistic that we can have a very effective combination of delivery (lipid nanoparticles) and cargo (Prime Editing and ePEG RNA). Of course, more funding will enable us to advance more quickly, particularly as there are many ways to optimize the lipid nanoparticles, and the lipids are very expensive.
Q: Can prime editing also be used in those with malformed CFTR proteins (they exist but work poorly) to create properly formed proteins?
Dr. Lands: The malformed CFTR protein is due to a mutation in the DNA. This mutation results in a messenger RNA that encodes alterations in the amino acid sequence that makes up the protein. So, a mutation in the DNA will results in an altered protein, in some cases a malformed or malfunctioning protein, in some cases, with a premature stop codon (message), then no protein (mutations whose name ends with an X). So, correcting the mutation in the DNA with Prime Editing will result in a correct messenger RNA and so a correct protein that will function correctly. In summary, the answer is yes, Prime Editing correction of the DNA will correct mutations that result in malformed and malfunctioning CFTR proteins.
Q: Is this envisioned to be a one-time or ongoing therapy? In other words, will the body break down the prime-edited particle and need to be replaced regularly or does it create a more permanent change in the body's ability to create CFTR?
Dr. Lands: Our goal in delivering Prime Editing to lung airway cells is to target those cells called airway basal cells for a long-lasting effect. Airway cells turnover and are replenished (much like when you scratch the inside of your cheek, it repairs itself quickly), with the basal cells being responsible for replenishment. If we can successfully Prime Edit the DNA in the basal cells, then we should have a long-lasting result. Others have delivered CRISPR (the earlier less efficient form of Prim Editing) in lipid nanoparticles to mice targeting the lung basal cells and were able to demonstrate a very long-lasting response. So, we are optimistic that we can achieve this with our lipid nanoparticle Prime Editing strategy. We will develop both inhalable lipid nanoparticles and those that can be injected intravenously and compare these two delivery strategies.
Q: Other than financial support, which we’re doing now, and fundraising – what else can we do to advance this research?
Dr. Lands: We are very appreciative for the funding received and the initiative of CF Canada to partner with Génome Québec. However, funds are limited. We are trying to leverage this funding. For instance, Dr. Lands has applied to the Canadian Institutes of Health Research (CIHR) to explore more options of lipid nanoparticle formulations-news to come in the next few weeks. Dr. Lands is also an applicant on a Canadian Fund for Innovation application to develop RNA therapeutics, where he co-leads the RNA delivery theme-news to come late autumn. Dr. Lands just received a small grant from the Research Institute of the McGill University Health Centre to assist with lipid nanoparticle development. Another way that can help advance this research is Dr. Lands’ membership in a large McGill University-led consortium (D2R, DNA to RNA) that enables interaction with Canadian leaders in multiple universities around lipid nanoparticles and RNA chemistry, as well as industry collaborations.
[1:21:40-1:25:22] Dr. Rachel Syme, Program Director, Research and Clinical Trials, Cystic Fibrosis Canada
During a brief Q&A session, Dr. Rachel Syme spoke about Cystic Fibrosis Canada’s clinical trial network – CF CanACT – and its vision of ensuring Canada is a preferred site for CF clinical trials by bringing together Canadian CF clinics to increase capacity and enhance participation. Dr. Syme provided valuable insight into various clinical trial resources and where to access them, the application process, the different requirements for participation, and the unique timelines associated with clinical trials.
If you would like to learn more about CF CanAct and accessing clinical trials, visit the CF Canada website.
Recordings
If you were unable to attend CF Canada’s Community Forum on June 18th, we’ve got you covered! Please find recordings of the forum in both English and French below.
For English recording, click here
For French recording, click here
Stay tuned for CF Canada’s 2026 Community Forum – you won’t want to miss it!
Please direct any new questions to info@cysticfibrosis.ca
Cystic Fibrosis Canada thanks you for your continued support.