Yale Medicine pediatric pulmonologist, Dr. Marie Egan, MD talks about a new therapy to treat cystic fibrosis.
Interview conducted by Ivanhoe Broadcast News in 2022.
For our viewers who’ve heard of cystic fibrosis but may not have a good understanding of what’s happening, tell me what’s going on with a child with cystic fibrosis?
EGAN: Sure. So cystic fibrosis is an inherited disease, and when a child is born often they appear to be completely healthy. Sometimes they can have difficulties with their intestines and digesting their food right from the get-go. But it’s a disease that affects the lungs, the respiratory tract, the sinuses. It can affect the GI tract, or your intestines, how you digest food, how you break it down, and then how you can then use those nutrients to grow. It can also affect the sweat gland. So many of the organs within the body are affected with it.
What happens is a child gets older, if there is no treatment? Does it depend on the severity of their disease?
EGAN: Well, normally you see symptoms pretty quickly. So most children within the first couple of weeks of life will start to develop some problems with the GI tract. They can also develop some problems with mucus and cough so that they will get into trouble with bronchitis, pneumonias, cough, and they will also get into trouble from the digestive standpoint in that they won’t be able to digest food and then they will have something called failure to thrive, where they’ll eat but they won’t get any weight.
Is this a condition where treatment’s necessary?
EGAN: Absolutely. Within the U.S. and many countries now too, there’s newborn screening done for this disease so that children are picked up by newborn screening soon after birth within the first few weeks so that we identify children who have this disorder before they become symptomatic. Before they have trouble, we know that that keeps them healthier and works much better for the overall health and their longevity.
Is it life-threatening and can it be fatal?
EGAN: Yes and yes. If it’s not treated, it is life-threatening and fatal.
And what kind of treatments? Is it medical? Is it surgical?
EGAN: For the most part, it’s medical treatments. As I mentioned very early on, there are some children who present as newborns with trouble with their intestine, and that can actually be a surgical intervention. But for the most part, it’s treated medically. Daily medications, daily therapies, so it’s a lot of energy and effort by families and by patients. But with most of these interventions, the life expectancy, and the life course, and the quality of life for patients has changed quite dramatically.
Are there risks to somebody’s medications? Is this a quality of life issue where these kids on a lot of these medications?
EGAN: The medications are essential, but there’s pluses and minuses to everything. And I think the other piece of it is, it’s a lot on a patient who is generally healthy. So you could come to our clinic, we have a CF center in a clinic. You could see our patients and you will take a look at them and you say, “My goodness, they look like they’re completely healthy children,” and that may be true. But the healthy appearance is- and generally they might be healthy is because of all the therapies they do. When you’re health- when you’re well with CF, and not having some of the complications that we see, your daily care, or the therapies and meds that you need to do can take 2.5-3 hours a day. So think about that. Think about your busy life. Think about your children’s busy lives. How hard is it to schedule everything? And what I’m asking patients to do to stay well is 2-3 hours a day of treatments, and then they’ll stay well. But it comes- so quality of life, even with these great medicines that we have is hard.
Is there a cure?
EGAN: There is no cure at this point. There are newer medicines that can stop the progression of the disease, or slow the progression of disease, but there is no cure for anybody. Some of the children and adults who have this disease, there are some newer- there is a newer class of drugs that we have that can treat the complications and the manifestations of the disease. But not all of our patients can take those medications because it’s a genetic disease and these medications are specific for certain mutations or certain ways the gene goes wrong.
Are you and your colleagues looking at attacking this disease at the genetic level?
EGAN: Sure. So if you really want to cure a genetic disease, one might suggest that the best way to do that is to fix what’s gone wrong in the gene. When we think about genes, I think about them as the blueprint of how to make you, how to make you the person you are. So if there’s an error in the blueprint and the instructions, that can affect pretty much every part of you. And some of those- and for some of those mutations, it can affect GI tract, your lungs. And so if we could figure out how to fix that error in the instruction booklet, then perhaps we could really cure you of your cystic fibrosis. Ideally, you’d want to think about trying to do this as early as you could because we know that if you can correct it early, before there are a lot of the consequences of the instruction booklet going wrong, the gene going wrong, then we can often bypass or get rid of all of the complications and we could cure you.
Are you and your team looking at gene editing technique? Can you explain what that is? And can you tell me which?
EGAN: Sure, when we think about how do you fix a genetic problem. Like I said, the best thing to do would be to fix what goes wrong in the gene. So in the past, when we think about that, many people talk about, we’ll just give you an extra copy of that gene, and that would fix it. What we’re doing is really going to look at your gene and trying to find the exact place in the gene where there’s an error. And then we’ve designed special therapeutics that can find that error attached to the gene very close to where that error occurs. And then harness your own body’s ability to repair your genes. Everybody’s cells, everybody’s body can repair little errors in your DNA. It’s essential in order for us to stay well. So we have designed these small molecules that can call in those repair systems in order to fix the gene. So if we use those small molecules we design, we include a small piece of DNA or blueprint that has the right instructions. Your own body can fix itself.
What is it called? Does it have a special name?
EGAN: Well these are called chip flecks forming peptide nucleic acids and DNA nanoparticles. Triplex forming Peptide Nucleic Acids or PNAs, DNA nanoparticles. The too little the template or the blueprint is the DNA. The PNA is the special therapeutic we design, and then we have to package it into a delivery vehicle, which is the nanoparticle.
Would that be given as an IV or given as an oral medication?
EGAN: So we have given it two different ways, one way is to deliver it straight to the lungs. Since cystic fibrosis is a disease where we know that your lungs are very involved. We can deliver it that way but the most recent research is by delivering it IV, because there’s a lot of things that go wrong and cystic fibrosis, there’s a lot of organs that are affected. It’s not just your lungs, it’s your GI tract, It’s your pancreas not only the digestive part, but the part that makes insulin diabetes can become a compilation. If you give it via a vein, it can get all over the place. So the idea is to get it all over the place to all the organs that are affected. And also be able to target certain cells in the body that we know are important because they’re the ones that keep dividing and repopulating the surfaces of your organs, which over time those cells that cover the surfaces often go away. They get old, they shed off and we have to have new cells there. So we want to be able to deliver this to a cell population that will keep delivering.
How far away are you from human trial?
EGAN: I’d say we’re quite a ways away yet. You’ve got to make sure things like this are safe. We need to make sure we get the efficiency high enough that when we give it to people, we’d love to be one and done. So repeated dosing can happen, but you really love to be able to see if you could get the efficiency higher. So we have to also make sure that as we deliver these things, that your body doesn’t identify them as abnormal now. And then cause you to have lots of inflammation. So there’s lots of things that we need to check on before we get there.
What are the implications of being able to have something like this?
EGAN: Well, there’s a couple of things that are really important for some of our patients. As I said, we had this new class of drugs it’s really great for large number of our patients because even though they have to take it every day, really makes their protein that’s affected in CF called the cystic fibrosis transmembrane conductance regulator protein, or CFTR, work pretty well. But there are about somewhere between 10 and 15 percent of patients who don’t have a mutation that can be fixed by those small molecules. So for them, there is not a new miracle drug. So anything we can do to move these nucleic acid therapies ahead, it’s going to be really important for that population. And I think it’s also really important for us to think if we could deliver these therapies to folks very early before there’s all the consequences of having a CFTR protein that doesn’t work without scarring of different organs, we could really potentially cure this disease and make this something that people don’t have to spend three hours taking care of every day.
Is there anything that you would want to make sure people know either about cystic fibrosis or about the research?
EGAN: I think that for cystic fibrosis, it’s a disease that for many people will note that it’s been in the news when we have these new medicines. And I think a lot of people look and say cystic fibrosis, it’s already fixed. What are you doing this all for. But I think that it’s not all fixed for everyone. And I think living with a chronic illness is something my patients do bravely and every single day and live life to the fullest and there to be admired. But if there’s a way to really decrease that human suffering without the burdens of hours of therapy, the worries and the complications of medications. I think it’s imperative that we move forward and not just for CF, but for all genetic disorders.
END OF INTERVIEW
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