Rebecca Ahrens-Nicklas and Kiran Musunuru Transcript — Nov. 17, 2025
Rachel Jones/NPF (00:00:02):
We’ll start the second session of day one of the Rare Diseases Reporting Fellowship with an introduction to baby KJ Muldoon, an infant born with rare disease in the US state of Pennsylvania. Here’s a clip from a video produced by the Children’s Hospital of Philadelphia
Speaker 2 (00:00:30):
Five weeks before KJ was supposed to be born, and Nicole called me and said, we got to go to the hospital like now, I don’t know, six hours later, KJ was here. He was beautiful. Little boy,
Speaker 3 (00:00:42):
Little creamy,
Speaker 2 (00:00:42):
Yeah, in that moment just seemed everything was fine. He was born on Thursday and then a doctor comes in Saturday morning and says, Hey, listen, there’s some things we saw that we didn’t like. We were obviously very concerned, but we had no idea what we were in store for.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:01:05):
He was born at the adult hospital at the University of Pennsylvania and a very astute doctor at Penn actually checked his blood ammonia level, which is a marker for some of the metabolic diseases that we think about, and it was very, very high.
Speaker 2 (00:01:18):
We were sitting up there and one of the doctors came to us and said, we think we know what’s wrong. Your son is very sick, but the best place in the world for your child to be when he is very sick is next door. And I’ll never forget that for the rest of my life,
Speaker 3 (00:01:36):
We would do absolutely anything for our kids. So it wasn’t like a woe is me. It’s okay. This happened to us. How are we going to support him?
Rachel Jones/NPF (00:01:52):
Thank you, Syd. Researchers, Rebecca Ahrens-Nicklas and Kiran Musunuru of the University of Pennsylvania and Children’s Hospital of Philadelphia collaborated with Innovative Genomics Institute to develop and perform the historic CRISPR based gene editing therapy for kjs condition. You can read their full and impressive bios on our website@nationalpress.org, but we are greatly privileged to have you joining us today. Thank you so much.
Kiran Musunuru/Children’s Hospital of Philly (00:02:34):
Our pleasure to be here.
Rachel Jones/NPF (00:02:35):
I’m going to let you both guide. Thank you, Rebecca. I’m going to let you both guide the conversation, but I would like to start as a journalist by asking you to think back to the very first time you met Peggy kj and his parents, and start by painting a picture for us of how you perceive them and where you were in this research journey at that time.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:02:59):
Yeah, maybe I can start with that one because I had the privilege of meeting KJ and his family before Karen did. So I’m a physician and a scientist at chop, and my clinical practice involves taking care of patients with urea cycle disorders and other rare metabolic diseases. And so I was not on call when he was born. One of my really talented colleagues was on call, and so she and a lot of our fellows and trainees and nursing staff and dieticians were the ones who really stabilized him and got him safely through those initial first few days of his life that were very dangerous for him than really first few months of his life. I met them a little farther along the way. I had known all about him because as part of our clinical team, we all share cases together and talk about the best way to care for our patients.
(00:03:53):
It’s a small community of physicians that do what I do. And then I had the privilege of meeting the family for the first time, I guess when he was about eight weeks old, somewhere around there. And I had purposely, I’ll be honest, stayed away. I knew that we were working on this research idea and I wanted to make sure that before I spoke with them, we actually had a plan in place to try to see whether or not this type of therapy would be possible for them. So we had done a lot of work in the lab, and Karen and I can talk about that if that’s of interest to people, but it was only once we had a plan for how we might actually move what we discovered in the lab into the clinic for the first time that I spoke with kjs family and met them. And so I met them along with some of my other clinical colleagues, and I had a wonderful conversation with kjs parents, and I had met KJ previously and examined him and knew him as the little baby that he was, but the first interaction with his family, with his parents was quite amazing.
(00:04:57):
They had no idea that we were trying to do this, trying to develop a gene editing therapy for their child. It was all done a de-identified way up to that point. But I came to them and I said, listen, I know that this is going to sound crazy, but we think that we have figured out a way to correct the genetic misspelling that has led to K J’s disease. I have no idea at least we can do it in a lab. I have no idea what that means in terms of whether or not it might work in a person. And we had a really good conversation about their goals for their child, about science, about medicine. They are a very loving family with, this is obviously in the press. They have other children, they’re great parents, and they were trying to balance the needs of their child to make sure they could give KJ the best shot that they could with the goal of advancing science and advancing medicine for other kids.
(00:05:55):
It was pretty amazing. They asked a lot of good questions about what this meant for their child, but very quickly pivoted to start asking, what does this mean for the greater urea cycle disorder community and the greater rare disease community? And so in that first conversation, they agreed that we should keep going with the scientific research. Obviously, they were not ready to say yes if we’re going to give an experimental drug to our child, but they appropriately so. But they were encouraging that we move forward. And from that moment on, we’ve been partners in all of this. So I would give them regular science updates and research updates, and they became full partners with us throughout this whole process of us trying to develop this therapy. I will tell you, he also received what we considered our standard of care for treatment of urea cycle disorders at chop. So he was admitted to the hospital this whole time, so they were balancing their lives, they were balancing their jobs, their other children while having a sick kid in the hospital. And they have done an amazing job through all of that. And so it’s been a real honor to partner with them. They’re quite amazing, as you can tell, even from that short snippet of video. Karen, I don’t know if you want to add in more.
Kiran Musunuru/Children’s Hospital of Philly (00:07:06):
Sure. Well, I had quite a different experience, and that is because I’m also a physician. I’m also a scientist like Becca, although my clinical practice, the patients I treat are actually patients with heart disease. I’m a cardiologist, an adult cardiologist, so I take care of not newborns or children, but actually older individuals, adults typically, or elderly patients who have had heart attacks, heart failure and things of that sort. And I’ll explain how that ties into this story because there is actually a very important connection there. But my experience with KJ and his parents was quite different because I was working across the street at the University of Pennsylvania in the laboratory helping to develop therapy. And Becca and I both felt that objectivity was important, that there was a need for separation so that at least one of us was cued, so to speak. We didn’t have any sort of attachment, emotional or otherwise to the patient, to the family, which is understandable because as soon as you meet kj, you immediately form that bond with him.
(00:08:10):
He’s just such an adorable little kid, such a happy kid, but wanted to be clearheaded and be able to make rational scientific decisions about the development of the therapy. There were no go decisions that had to be made. Were we going to go further with this at various milestones along the six month development process? And I think to flip it around, I think Becca was concerned that if K J’s parents knew people who were directly involved in making the drug and going to quite a lot of effort to make this happen, that they may feel inhibited in their ability to make a clearheaded decision about whether they would want their child to receive the therapy. They might feel that they owed us in some way because of the work we had into it. So we felt strongly that that separation needed to be maintained. So I actually didn’t meet KJ until a few days before he received the treatment, and I didn’t meet kjs parents at all until the actual day and time of treatment in the room when he was getting the first treatment, although I’ve gone to know them quite well since then.
Rachel Jones/NPF (00:09:15):
Let me ask both of you to address something that I am always fascinated by, and that is you’re a part of this historic, innovative technological advancement and you are having to talk to parents who aren’t scientists, who aren’t doctors, who really, in many ways, you’re talking a totally foreign language to them, but tell us about as scientists, as human beings, as individuals, what it’s like for you to have to go to those parents and say, trust us with your baby. We’re going to try something that in their minds possibly could kill him. Tell us about that process and how scientists move through that.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:10:05):
Yeah, I think that it’s important to realize in the rare disease world that I live in and the kids I take care of, I often meet patients. We have a newborn screening program in the United States. A lot of the disorders I care for are picked up by newborn screening. So I’ll meet a family when their baby’s five or six days old, not too different than when our team met KJ and kjs family, and inevitably the family has never even heard of the diagnosis that their child has. This is a foreign language. They have no idea. I mean, no one knows what the diseases are that I care for. In all honesty, there’s some that I even have only seen once or twice. And so it is an entirely new language, not just about therapies, but about the disorder itself. But it’s amazing because families and parents, as I think we all do, when we think about what’s best for our kids, arm themselves with knowledge.
(00:10:59):
So very quickly, I’ve seen this over and over again, regardless of the educational background, regardless of the field that they work in, regardless of their background, parents want to understand what’s happening to their child. It makes sense. And so part of our job, and it’s actually part of my job that I love the most, is to help educate families around the diagnosis and then around what potential therapies are out there. And so that process, we had done a lot with kjs family and they were amazing, and they asked great questions. I mean, I still remember the whiteboard in their room. There’s biochemical pathways of the urea cycle and what’s broken and what happens. And very quickly they become the experts to the point where they’re asking really, really astute questions. And they were amazing in that regard. So then you throw on top of that the discussions around therapies.
(00:11:51):
And I will tell you that this family, in addition to most families I care for arm themselves with really great knowledge, not only obviously from the internet where a lot of people look up what’s available for my child, which makes perfect sense. But in speaking to other families, they had a really good grasp from our team, from our interactions, from my colleagues’, interactions from other resources that they had encountered what it would look like for a child to have a liver transplant, which was the alternative in our practice for the therapy, the experimental therapy that KJ received. So that was their baseline understanding. And then you have to educate about gene editing, which was a process, and it was not a process that happened in one day. It was a process that happened over months, and it wasn’t just done by me. We would have multidisciplinary team meetings where different people would talk about different aspects of what an experimental therapy is, about, what the pros and cons might be.
(00:12:44):
I thought it was really important that they heard from everyone that was involved in this decision. And little by little, they became real experts in the possibilities and the science and what this meant, the pros, the cons. Really this is all part of the informed consent process, which for something like this can’t happen over the course of one day, it happened over the course of months and multiple interactions. I think the hardest question you ask is how do you hold that responsibility as the person who’s offering this to their child and what does that do? And I will tell you it’s really hard. And part of what I felt I needed to do was to make sure that the plans that we had laid out to ensure that this drug was as safe as we could possibly make it. Again, it’s research is never perfectly safe and well thought out was by seeking the advice of others and seeking the input of others on our preclinical data.
(00:13:34):
And so all the data that supported us moving this forward, I wanted to make sure that other people thought we were doing the right thing. And so having an oversight committee, which is something that I really appreciated that we built early on to sort of evaluate the data critically to say, yes, this is appropriate to offer the family or no, it’s not appropriate, helped sort of a second set of third, fourth, 10th set of eyes on what we were trying to do. But I will tell you that responsibility is something of offering this to this family is something that is, I’ll be honest, it’s weighed on me. It has been a huge undertaking this year and something that I’ve tried to be very thoughtful and ethical about, but it’s been hard. You don’t want to do harm as a physician. That’s our primary goal, is to do no harm in every day to even today, every single moment that I think about this case, I worry about the potential for harm now and down the road he’s doing very well, knock on wood, but it’s something that I will always be thinking about. I don’t know, Kieran, if you have stuff to add, but
Kiran Musunuru/Children’s Hospital of Philly (00:14:38):
Yeah. Well, I would take a step back. Obviously wasn’t in the position that Becca was. I wasn’t directly interacting with K J’s parents, but I think Becca and I both benefited from the fact that we’re practicing physicians. And so the idea of having to ask patients, ask families to put an enormous amount of trust in us, it’s not foreign, right? It’s something we actually do day to day in our everyday practice. For example, I take care of patients who have had fairly devastating events, like massive heart attacks and things of that sort and have to have conversations about the various options. And some of those options are potentially very hazardous, like bypass surgery. I mean, we tend to think about it fairly casually because so many people are getting bypass surgeries nowadays, and it’s almost become routine in every day, but it’s not a risk-free procedure.
(00:15:29):
There is a not insignificant chance of something going wrong during bypass surgery. And so I think we’re used to maybe not comfortable what we’re used to. The idea that we have to present some pretty complex choices to patients. You can be very conservative, but there’s potentially not as much to be gained in terms of health if you take a conservative approach versus taking something that’s much more aggressive such as cardiac catheterization or even major surgery, bypass surgery, things of that sort and weighing the pros and cons. And ISBE alluded often the best strategy is not to have any one person having that conversation, but people having that conversation. So pretty frequently when I find myself in these situations where we’re trying to make a decision, do we do nothing and just treat with medications? Do we do major open heart surgery to replace the valve or do we use the newer valves that can be deployed versus catheters, although they’re still semi experimental and don’t have the track record that opens heart surgery, does. We have what we call a heart team come together. That’s cardiologists like myself, that’s cardiac surgeons, heart surgeons, a team of people who really span all the various types of expertise to be able to meaningfully have that discussion as to what is the best choice for the patient in front of us.
Rachel Jones/NPF (00:17:00):
Let’s take a moment here to maybe get a sort of primer on crispr. I remember when it was first announced and I first started reading about it, it seemed fascinating to me to be able to sort of edit a gene. So can you help the journalists understand the background and how it came to be and what it means?
Kiran Musunuru/Children’s Hospital of Philly (00:17:22):
Certainly. So CRISPR is not something that was invented per se. It has actually existed across many, many, many bacterial species for billions of years. It evolved as sort of an immune system for bacteria. The idea is that bacteria just like we have to fight off invaders, microorganisms, pathogens that are trying to invade our body and grow in our body and reproduce and so forth, it turns out in the microscopic bacteria deal with the same sort of threats just on a different level. So in their world, viruses are the big threat. And so they have evolved ways to help them.
(00:18:01):
If they see a virus for the first time, they can’t do much about it. They either survive it or not. But if they survive it, then they take little snippets of DNA sequence from that virus and incorporate it into their own genome. And they have a system called CRISPR that allows them to use those little snippets and monitor for any repeat infection by that virus. And if that same virus shows up and has a matching DNA sequence to the snippet that was stored away from the past encounter, it can use crispr, the bacterium can use CRISPR to actually search out and destroy, if that’s the right way to think about it, that foreign sequence, that invader of the virus. And so that’s how CRISPR developed as an immune system. And then fast forward billions of years, some very, very, very talented scientists figure out that this existed and then unraveled how it worked.
(00:18:51):
And that whole process took on the order of, well, it’s still going on, but I would say on an order of 15 to 20 years from beginning to end, before we actually had a version of CRISPR that we could use for unquote gene editing, actually editing human genes in human cells in our bodies. And so how does CRISPR work? Well, something that’s important to understand is that there are different flavors of crispr. It’s not one single technology. There’s actually what you can think of as a version 1.0 and then a more sophisticated version 2.0 and 3.0 and so forth. But the best way to think about CRISPR is think of the entire human genome, all 46 chromosomes that’s in every single human cell as a textbook, and each chapter is a chromosome. And within each chapter you have a lot of paragraphs, and each of those paragraphs is a gene and you want to affect, you want to change, you want to edit one of those paragraphs, one of those genes in order to have it do something different or read differently than it originally did.
(00:19:54):
And so version 1.0 of CRISPR is often compared to a molecular scissors. But what I actually think is a better analogy is let’s say you want to take that paragraph and basically remove it or obscure its meaning so that it can no longer be read the equivalent of turning off a gene in the body, if you will. Then you can think of CRISPR 1.0 as basically tearing, and then obviously you don’t like to have, so then you tape it back top. But you can imagine if you tear it really roughly and the edges become very frayed and then you try to put it back together, you lose some letters, you scramble some sentences. And when it comes to gene editing, that is actually a feature, not a bug. You are actually trying to obscure paragraphs. You’re actually trying to turn off genes. And so this very crude process where you’re tearing and taping it back up together, that’s what’s happening in the cell.
(00:20:46):
CRISPR will find the gene, it has a GP slike component that tells it go look for the sequence. And that GPS component is really an adaptation of what I described earlier, this idea that bacteria can take snippets of DNA that they’ve seen before, and then look for that same sequence again the next time a virus invades the cell. It’s the same sort of mechanism, this GPS except now we’re repurposing and saying, Hey crispr, go find this particular gene, this particular sequence, and make a cut there. And so it cuts the chromosome, it cuts through the DNA, the cell doesn’t like having broken DNA, it tries to patch it up, but often makes errors. And if those errors occur in the gene, it basically turns off that gene just messes up that gene. Okay, so that’s version 1.0. Version 2.0 is more sophisticated. It’s much more like what we think of as a pencil and eraser.
(00:21:38):
And the idea there is, let’s say you have a paragraph, but there’s a typo, there’s a misspelling, and that’s obscuring a meaning of a word and then ultimately the meaning of the whole sentence, the whole paragraph, it’s a gene that’s not working properly. And in K J’s case, he had one of these misspellings, actually two misspellings in both copies of a particular gene. And that gene makes an enzyme that’s important for metabolism, that’s important for properly baked, breaking down protein that’s ingested in the diet that’s eaten because that enzyme is broken. That means that wasn’t able to clear the toxic metabolites from the protein. He ended up with a very high level of what’s one of the waste products of protein, which is ammonia. And if it sounds like ammonia is a bad thing to have in the body, it is normally you have a string of enzymes, six enzymes in a row that turn that ammonia into urea, which is a benign metabolite that can be passed out of the body through urine.
(00:22:40):
In fact, that’s why urine is called urine because it has a lot of urea. But with his broken enzyme can’t break down that ammonia. It builds up in the body and becomes life-threatening. We can talk more about the consequences of that disease, but with version 2.0 of crispr, which is what we know as base editing or what we’ve come to call base editing, what you can do is if there is a single letter that is misspelled in a word, in a sentence, in a paragraph, a single misspelling in a gene, what we can do is use base editing to correct that single letter misspelling. So change that letter into another letter. So again, pencil and eraser. And you can do it very precisely out of the 6 billion letters that are in that entire textbook, we can find just the one letter that needs to be changed and corrected.
(00:23:28):
We have that degree of precision. So that’s version 2.0, and that’s what we ultimately use in kjs case. And now there’s a version 3.0, which is the newest of all, and it’s even more sophisticated. It’s what we would consider to be a word processor, and that allows you to basically make any type of changes you want. You can change one letter into another letter or you can insert a letter, you can remove a letter and remove word. You can make all sorts of sophisticated changes that you ordinarily would do with a word processor that you wouldn’t be able to do with a pencil and eraser or even a typewriter. It’s the newest technology, it’s called prime editing, sorry for the pun, but it’s not quite ready for prime time. We’re still in the process of figuring out how to best use that to actually help patients, although we’re just starting to see it.
(00:24:13):
And I think next year or the next two years, we’ll really start to see prime editing being used in patients. But for now it’s the latest and least developed of the gene editing technology. So those are the three versions. You have a molecular scissors, it’s very crude, but if you just want to turn off a gene, it can work quite well. Then there’s the pencil and eraser base editing that allows you to fix a misspelling and one letter misspelling by changing it into another letter, the correct letter. And then there’s prime editing version 3.0, which is the word processor, which will eventually let us do a lot of more sophisticated things.
Rachel Jones/NPF (00:24:50):
Rebecca, can you give us an idea of the duration of this process? You meet kj, you talk to his parents, you tell them what you want to do. How long did that process overall take from beginning to the point at which you saw he was starting to benefit from this process?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:25:13):
Yeah, I will say this process happened in sort of phases. First, the process before Katie’s family knew anything about this. So from the time he was born until the time we felt we had a solution in the lab, and that was about six to eight weeks. Then we had a period of time from when we had talked about this possibility with the family until we gave him his first dose. And his first dose was given right before he turned seven months old. So that timeline was about five months. So by the time he was seven months old, we had permission to give, we had made the drug, we had tested the drug, we had permission from our regulatory body, the FDA, to be able to give this to him. And this is what we call in the United States, a single patient expanded access experience. So what that essentially means is the ability to use a drug in a single patient and experimental drug and a single patient for clinical care.
(00:26:10):
So it’s not a formal clinical trial. So to the point of your question of when did we first start seeing definitive benefits, I can tell you what we observed, but I want to hesitate to say that this is our experience with one patient. This is not a formal clinical trial. And so we observed very quickly within, I dunno, so we dosed him right before he was seven months old. We provided the first dose right before he was seven months old and within a week or two, we could increase the amount of protein that he took in his diet. So kids with this disease, one way you help treat them is you restrict how much protein they take. And very quickly, within about a week, we were able to get him up to the recommended daily allowance for protein for a baby his age. And this is really important because protein is necessary for babies to grow.
(00:26:57):
And so we had hints that something might be helping him very quickly. And then he went on to receive two subsequent doses over the course of the next couple months. And he was discharged home when he was about 300 days old. And we continue to follow him closely. And I will say, I think that through this process we continue to see signs that he has benefited from this therapy. But to make definitive conclusions, like I said, is hard. But the timeline in general is that we had an editing solution by six to eight weeks after he was born. We were able to give him his first dosage of the medication before he was seven months old. And then he stayed in the hospital a couple more months getting subsequent doses, and then he went home to his family. And that has been our timeline,
Rachel Jones/NPF (00:27:43):
Describe what the medication is, what form it takes and how it’s administered.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:27:49):
So it’s an IV infusion, so it’s an IV medication that we give around over two hours, and then a little bit of what’s called a flush afterwards. So after over a couple hours goes into his bloodstream. And the medication itself is just a solution that has these soap bubbles that essentially inside those soap bubbles have the components needed to the CRISPR components that Kieran was speaking about that are needed to correct the variant or the genetic mutation that causes this disease. And so inside the soap bubble, there’s two things. There’s that editor, so an RNA that makes the editor that the pencil and eraser that Kieran spoke about. And then there’s a guide RNA, which essentially is the GPS signal telling that editor where to go edit. So you give this infusion, these soap bubbles are taken up by the liver where they tend to go, they do their job and actually they’re cleared out of the body very quickly.
(00:28:41):
So within a couple days the drug is gone. And so if the editor worked, the edit will have been made and that edit, we anticipate that change in the genome will be durable. We hope it will. We’ll have to see over time in humans whether that’s the case. But in animal models, we see that that correction is there, right? It changed the genome, it changed the patient’s DNA. And so as for example, a baby’s liver grows because obviously a liver is going to change in Latin size from seven months old to a fully grown adult. As those liver cells divide, it passes on that change, that edit that we made in the genome. So we are hopeful that any correction will be durable, of course, only time will tell, but that’s what we see from animal studies and from initial human studies.
Rachel Jones/NPF (00:29:29):
We’re going to open it up to questions eventually, but I am going to ask one for Simon ach. I think he’s from Canada, but he asked what percentage of the cells does it need to reach and successfully correct in order to treat the disease?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:29:48):
Yes, Karen, I dunno if I see you. Unmute yourself if you want to go ahead.
Kiran Musunuru/Children’s Hospital of Philly (00:29:53):
Yeah. So I think it’s important to understand that the soap bubbles that Becca mentioned, this treatment, it really just goes to the liver. It doesn’t go through the entire body. It doesn’t go into the germline, for example. It’s not something that could be passed on to the next generation. And that’s important because the liver is where the action is here. So in K J’s case, he had the broken enzyme in his liver, and if we could fix it in and enough of the liver that enough of the enzyme working again by making this spelling correction, then that would be good enough to greatly improve his disease. It did not need to be every single one of his liver cells. It did not need to be even 50% or half of his liver cells. I think our estimate is 10 to 15% would do the job.
(00:30:39):
And I think that’s what we achieved. It’s a little bit hard to tell. The only way to know for sure is to actually take a biopsy of the liver and then actually measure what’s going on in the cells. But that’s a very risky procedure. And the truth of the matter is KJ is doing so well now, he’s so healthy that it’s considered unethical like the IRB, the institutional review board, the ethics committee said, no, that’s not really something we can do in kj. So we’ll never have that certainty as to exactly how many liver cells we corrected, but we knew coming into it that it would not need to be the vast majority of them that a relatively smaller proportion, say 10 to 15%, might be enough to greatly improve that disease. And it does seem like by getting enough of the enzyme working and enough of the cells in the liver able to keep the ammonia levels under control just as any healthy individual is able to do so after they eat a lot of protein in the diet. And so it does seem like to some degree that the therapy did what was intended.
Rachel Jones/NPF (00:31:38):
I’m going to open it up soon, but I have one more question that is about this expedited process of getting to do this kind of procedure. Is it realistic to think that, excuse me, we are moving towards an era that maybe we’ll be able to do that more frequently or will there continue to be challenges to have this kind of procedure available broadly? Is it something that you worry that maybe there will be a complication that crops up at some point that totally disrupts this process?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:32:17):
That is a great question. I think that, and part of the reason I wanted to highlight that this is what’s called an expanded access investigational drug application here in the us. Part of the reason I wanted to highlight that is that as I said, it’s not clinical research. It’s technically considered clinical care. And so in order to be able to fully generate that body of knowledge, really to measure whether or not this type of drug is safe and whether or not it works, we need formal clinical trials. And so that’s what Karen and I are trying to move towards. And we’ve released some of our thoughts about how we’re going to try to do this, but the idea is you need formal trials where you essentially assess multiple versions of this drug, right? Essentially the same drug that’s just tuned to an individual’s genetic variant, right?
(00:33:05):
Whether it’s patient A, patient B, patient C, they might have different genetic misspellings, but the safety profile of the drug is actually pretty similar across those versions of the drug. So we are working hard to launch a clinical trial that would assess the safety of this type of drug formally so that we can generate the data needed to say whether or not this drug should be approved. And in the United States, if the drug is approved, then you can actually start talking to payers like insurance companies about reimbursement and how to scale this because it would be a shame if we don’t formally assess the safety and efficacy of this type of drug, and if we can’t scale it to help more kids and more patients. And I think it’s really important that we generate the body of knowledge necessary essentially, to gain those approvals if it’s appropriate to do so once we learn from the clinical trials. So that’s what we’re trying to do.
Rachel Jones/NPF (00:34:02):
Let me jump in here and ask Shji Huang, are you on mic? And could you ask your question?
Shji Huang | South China Morning Post (00:34:13):
Hello? Can you hear me?
Rachel Jones/NPF (00:34:15):
Yes.
Shji Huang | South China Morning Post (00:34:17):
Okay. Just a question about complication of the crispr because I’m, I’m a science journalist in South China Morning post I have closing following the use of the CRISPR for treating the rare disease, but often heard the news that the clinical trial was failed for the complications, even the patient’s die in the case of kg. How do you patients prevent the complication as the KG is failed?
Kiran Musunuru/Children’s Hospital of Philly (00:34:51):
Do you want to take that back or should I,
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:34:54):
Why don’t you take first crack.
Kiran Musunuru/Children’s Hospital of Philly (00:34:55):
Okay. So what we did in K J’s case was something a little unusual, but we did it because we recognized that no kid, much less, no baby had ever received a treatment like this before. That said, by the time we treated kj, several hundred adults had received this kind of therapy, this gene editing therapy. So there was some sense of the safety profile. And generally it’s been pretty safe, although as you point out, there have been occasional complications and in very rare circumstances, death that might be due to the effects of the drug. But in kjs case, we took a stepwise. So if you were paying close attention to what Becca was saying, she said KJ received the first dose and then subsequently received two more doses before he left the hospital. So we did that deliberately. Instead of giving him one dose all upfront, we said, let’s make sure this is safe dose of the drug.
(00:35:57):
So we did the very first dose was very low. We weren’t necessarily expecting it to have much of a beneficial effect, but we wanted to make sure first and foremost that it was safe. So with a very, very low dose, we gave it to him and he had with it whatsoever, did very, very well with it, no safety concerns at all. And we did see a little bit of a benefit after that. And so then a few weeks later gave a second dose higher, still a low dose, but a higher dose. So stepped up in dose and he did very well with that and he showed even more improvement. So then several weeks later we gave a third dose, so now more like a medium dose. And then he was so doing so well, he was able to go home shortly after that. And as Becca mentioned, he’s been doing very well at home. So that’s the way we tried to minimize any complications, make sure we were being very cautious, and instead of giving them a medium dose or a high dose upfront and then potentially having a lot of risk doing it in the most responsible way that we could.
Rachel Jones/NPF (00:37:13):
Simon had a question, let me see if I can find it. It was about the costs. And if you had to sort of extrapolate or let us know how much it would cost for this kind of treatment, what would that be?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:37:29):
Yeah, I think that’s a great question and one that I think about a lot because if we’re going to scale this, we have to be able to pay for this to be able to help children and help patients. The cost for his specific case is actually really difficult to calculate because as I said, we built a team and a lot of people donated their time and effort. And so the cost of that time and effort, it’s hard to calculate. And so I would say I don’t think coming up with a number for his case is that informative. But I can tell you as we calculate the costs moving forward in the more realistic setting of first running a clinical trial and then hopefully someday having an approved drug product, it’s not as expensive as you might think. And we purposely to some extent chose urea cycle disorders, both because there’s a huge unmet need, but also there’s a pretty good understanding of the cost to treat a patient with the urea cycle disorder.
(00:38:27):
And our thought process was from a justification standpoint to payers, to those who will eventually hopefully reimburse for this type of drug, we had to essentially meet a benchmark and know what that benchmark is because it needs to be more cost effective than the current standard of care. And if you think about what the cost is for a patient with a urea cycle disorder in the United States, and I know that treatment is different around the world, and I’m happy to speak to that, but in the United States, one of the mainstays of therapy is something called a nitrogen scavenger medication. And patients take this until they get a liver transplant if they decide to get a liver transplant, the nitrogen scavenger medication itself in the United States that patients take is $750,000 US per year. It just went generic like a month ago. And they think the cost is going to come down to about half a million dollars per year, but that’s a huge cost.
(00:39:21):
And then you add on the cost of hospitalizations, which these children, even with standard of care, come to the hospital multiple times a year, which is expensive in the us, and you’re already at a very hefty bill, $750,000, a million dollars for a year without even factoring in the cost of a liver transplant. A liver transplant in the United States varies from center to center, but roughly an order of magnitude would be a million dollars. And so what our thought process is, is that if you could get the cost to manufacture and provide this medication down below a million dollars, it is a cost savings to the system. One thing about this class of medications, the manufacturing process of it is that it is definitely doable to get the manufacturing costs down below a million dollars. It is, I don’t want to say an easy drug to manufacture, but relative to some other cell and gene therapies, it is a much more straightforward chemical synthesis process. And so you really can think about ways of streamlining manufacturing to get that cost down. So while I can’t give you an exact number, avoid kjs case cost, I will tell you we have done the math and we think we can absolutely get the manufacturing process and the ability to deliver this type of drug down to less than a million dollars.
Rachel Jones/NPF (00:40:42):
Simon, forgive me for speaking for you. So I’m going to give you an opportunity to do a follow up with the researchers. You wanted to know about other families with kids, Simon.
Simon Spichak | Being Patient (00:40:55):
Yeah. So well, my question is that there’s going to be other families with kids that have something similar or a similar uria cycle disorder and they’re going to be coming to you because they see this on the news, they want to get this treatment as well. Are there regulatory or are there hurdles that prevent you from giving the treatment to them? How do you handle that conversation going forward now that you’ve treated kj, but there’s these other kids that could potentially be treated that you might not be able to treat?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:41:29):
Yeah, so we have been reached out. To answer your question, yes, families have reached out, thousands of families have reached out to us. They’ve reached out by email, by calls, by social media, you name it. Some of them have urea cycle disorder, some of them have other diseases. Some of the diseases that people have inquired about for their children or their patients, you’d have to correct organs other than the liver. So for example, rare neurogenetic neurometabolic disorders that I care for in my clinical practice. But right now the delivery is just not ready for other organs outside the liver. But even if you just focus on the individuals that have reached out to us with liver disorders that might benefit from this type of technology, we’re talking hundreds and there’s a huge unmet need and we know that. And so we cannot do in what’s called this expanded access one-off compassionate use approach for each of those children because the resources we would put into that would not be generating the data we need to get a drug approved down the road.
(00:42:31):
And so that’s why we think to be able to address the needs of all of those patients or as many of ’em as we can where it’s appropriate, the formal clinical trial we hope to launch later this winter will allow us to both help children through that trial, but most importantly, generate the data we need to try to get approvals such that there can be a sustainable model for all of these children that are trying to reach out. This is, while I say we’re trying to get the cost down, and we are, and I think it will be more cost effective than things like liver transplant. We are going to need someone to pay that cost. And in the United States that someone is payers, it’s insurance companies, it’s in other countries, it might be a health service, but we need to be able to show the data that is a benefit or that is a worthwhile use of health insurance resources, public health resources.
(00:43:19):
And so we are helping families to the best of our ability by scaling through a clinical trial to provide more access to more families and then ultimately, hopefully get an approved therapy which will ultimately allow us to scale. So yes, my patients, patients around the world, my friends and colleagues, patients, everyone is reaching out and we are trying to work as quickly, ethically, and robustly as possible to scale this for others. I dunno, Karen, if you want to add more to that, but that is literally all we are doing day and night these days is trying to scale to help more kids.
Rachel Jones/NPF (00:43:53):
We have an interesting question from Ferdinand. Ferdinand, are you there? Yes,
Shji Huang | South China Morning Post (00:44:00):
I’m Yeah,
Rachel Jones/NPF (00:44:03):
Please ask
Shji Huang | South China Morning Post (00:44:03):
Your,
Rachel Jones/NPF (00:44:10):
Okay. He may be having some challenges. He wanted to know about differences within families. So if the child has this condition and then other people are in the family are completely unaffected, what explains why this happened to this one child? And he wants to understand the mechanisms that determine who gets it and who doesn’t.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:44:35):
Yeah, that’s a phenomenon we see amongst patients, not just kids. I am biased, I take care of kids, so I say that a lot, but amongst patients with genetic diseases, and not every genetic disease has that same tendency or that same quality of having variability within families. There are certain genetic changes where if you change the genome, you’re just on the border essentially, that insults that difference is enough to put you close to having this risk factor for let’s say heart disease or lung disease or whatever organ we’re talking about. But you might need something else in either your genes or from your outside world to push you over the edge to fully having symptoms. A good example of that is some of the inherited heart disorders that you might see where maybe one individual has a very bad heart disease from a genetic change, but another relative in that family does not.
(00:45:25):
The diseases that we’re talking about here are a little bit different than that. These are what are called autosomal recessive disorders. So you have to inherit two copies of the genetic change, one from mom, one from dad, or both copies of the gene need to be broken. And what we see in this group of rare severe metabolic diseases is that if you’ve inherited both changes, if you have two broken copies of the gene, you will have the disease. There is a much clearer relationship between the genetics and the risk of disease here than there are for some other diseases. And that’s important. And it’s a really good question because if we’re going to take this risk, right, this is a risk to change, give someone an experimental therapy to provide a gene editing therapy. We want to make sure that the patient really has the disease.
(00:46:14):
And so part of what we and are going to have problems from the disease. So as we design this clinical trial that I spoke about, it’s really important to us that we make sure that we’re treating individual patients who either have shown us through their laboratory testing, through their clinical history, that they have a problem from this disease or that we are a hundred percent sure we’ll do so. And so we have to make sure that we are treating a genetic disease for a patient that needs that treatment. And so this severe catastrophic group of diagnoses that we’re talking about here, those patients really need our help. I agree for some of the different genetic diseases where there’s more variability, for example, between family members, we need to think thoughtfully about how we try to use these technologies. Does that answer your question?
Rachel Jones/NPF (00:47:01):
I hope so. I hope. Thank you.
Kiran Musunuru/Children’s Hospital of Philly (00:47:04):
If I could add just a little bit of color to that. So in kjs case specifically, he was entirely missing an enzyme in his liver, and that’s why it was so bad. So in order to be entirely missing the enzyme, both copies of the gene have to be turned off, have to be broken. So you get one from mom, you get one from dad. If you get a broken one from mom, but a healthy one from dad, you’re going to make half the protein. You should normally be making 50% of the protein. That’s just math because you have one good copy, one bad copy. And if you’re making 50% of the protein of the enzyme, that is enough to clear the ammonia from your body, you’re entirely healthy. The only way someone like AJ gets this disease is see if he gets two bad copies, a bad one from mom, a bad one from dad. Now you have 0% working protein, you have no protein at all. And that’s when you get into trouble because then you can’t do anything with the ammonia. It builds up in the body and is very toxic and causes a very bad disease.
Rachel Jones/NPF (00:48:09):
We have an interesting follow up question from Robert, from Kenya, Robert, maybe he’s not there. I’ll read it for him. Given that CRISPR treatment works by delivering gene editing components through an IV infusion that is cleared from the body within days, how confident are we that the genetic edit will remain stable and durable as the child grows, especially as liver cells continue to divide over time?
Kiran Musunuru/Children’s Hospital of Philly (00:48:44):
So I would say pretty confident. It’s hard at this point to be a hundred percent confident since we’re in very early days. There are only at this point a few hundred patients who have received this kind of gene editing therapy. But what we’re seeing in the adults who received the treatment 2, 3, 4 years ago now is that the editing appears to be entirely stable. So to give you a little context, some of the adult patients who have received therapies have received them for heart disease. As a cardiologist, I’ve obviously been very interested in what’s been going on in that respect. And I’ve actually participated in helping to develop some of those therapies for heart disease, reducing cholesterol levels, treating other types of heart disease. And what we see is that the effect, the therapeutic effect, for example, reduction of cholesterol levels or reduction of other proteins in the blood, they immediately go down after the patients get the treatment.
(00:49:44):
And then once they’re down, they’re down seemingly for a very, very, very long time, as I said, 2, 3, 4 years now, and there’s no hint that they’re coming back up. It really does look like it’s what we call one and done. Once you have the effect at the DNA level, even though the liver is still either growing or at least turning over some cells, they eventually die off. But the new liver cells are created from the existing old liver cells. It does seem like the editing is stable and that the therapeutic effect of the therapy, the desired effect is stable. So we can’t yet say that it’ll be good for the lifetime, but I think there is a very good chance that it will be good for the lifetime. And we’re expecting that in adults. And we’re also expecting it in children and infants like kj, but we’ll have to see to be sure.
Rachel Jones/NPF (00:50:38):
We have so many great questions, but we want to start getting us towards the goal line here by introducing the elephant in the room. And that is the fact that access to researchers who can talk about these issues with journalists access to the actual resources vary from country to country, from region to region. So what would you say to journalists, a journalist in Zimbabwe versus a journalist in New York City about covering this topic and ensuring that they get it right? What are the realities that people around the world will ever have equal access to this?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:51:25):
Yeah, I’m happy to start with that. I would take it a step further and say, access to care for kids with rare diseases, for patients with rare diseases is incredibly variable around the world right now. So let’s just take K j’s example. So take the gene editing away. If we had not provided gene editing to kj, his care would be a special metabolic formula. He required dialysis when he was born and then eventually a liver transplant. I will tell you that metabolic formula, which is life-changing, these medical foods for kids with metabolic diseases are not available in many, many, many, many places in the world. To the point where those patients that have the resources to travel, let’s say to the US or maybe to Europe for their care, will take back suitcases of cans of formula so that their child could have the lifesaving food that they need where they are.
(00:52:19):
Liver transplantation similarly not available everywhere at all. And so if we could develop a process by which one could deploy a one and done therapy, and I’m not saying that we’re there yet necessarily, but a one and done therapy that would keep a patient safe without having to undergo liver transplant and the ongoing management of liver transplant or needing medical foods across their lives that aren’t available in their home country, it would actually increase access in some ways. And we can speak a little bit to how we envision increasing access around the world, but one of the key components of this is the technology itself. As I said before, the synthesis and the manufacturing of this type of drug product is actually something that’s simpler in some ways than some other cell and gene therapies. It uses techniques that have already been developed for a variety of other usage and deployed throughout the world, including developing nations.
(00:53:24):
So the same sort of technology to make that soap bubble, to put the cargo inside that soap bubble that’s appropriate have been used to manufacture things such as vaccines. And those manufacturing sites are being set up around the world outside of just the United States or over Europe. And so I think that if we can repurpose those manufacturing sites at times to help develop this type of drug for patients locally, or if at the beginning patients are able to travel to a center for definitive therapy and then travel back to their home country, we might actually do a much better job in meeting the needs of kids with rare diseases around the world. So I worry about access all the time. I worry about access within the United States. I worried about access around the world, but I think by developing a cost-effective one and done therapy, you actually might increase access as compared to the current standard of care right now, which I have to tell you is incredibly difficult when you start thinking about access for patients around the world. Kirin.
Kiran Musunuru/Children’s Hospital of Philly (00:54:29):
Yeah, I would just second that and say there are different types of therapies. And so the first approved CRISPR therapy for sickle cell disease is actually a very, very intensive, both in terms of time and resources, very intensive procedure. It’s not even really a treatment so much as it is procedure. You take blood stem cells out of the body, you do the back into the body with a bone marrow transplant, the equivalent of a bone marrow transplant. So you’re talking months in the hospital, chemotherapy, the whole nine yards. That is why that type of therapy, even though it was a big milestone in modern medicine to be able to treat sickle cell disease, that’s why relatively few patients have received that therapy because it takes months and months of time in the hospital, chemotherapy, bone marrow transplant, that’s just not scalable. Even in the United States.
(00:55:25):
All the patients who could benefit from that therapy, very few of them are getting it. So that’s one kind of therapy. The other example I would point you to is the COVID-19 mRNA vaccines. They were effectively used in patients for the first time at the end of 2020. They didn’t really exist before that. So for the first time they were deployed in the United States, in Europe in late 2020. In 2021, it didn’t take that long to deploy those same vaccines much more broadly across the world. So that’s sort of a counter example. The first example with sickle cell, it’s not very scalable. It’s not something you could deploy across the world very easily. Whereas we have this example, and it was far from perfect. I understand that there are a lot of limitations, but at least in principle, you went from a brand new technology, an entirely new type of vaccine being deployed in high income countries, and then not that much of a delay really just months to a few years, to being able to deploy that more broadly across the world, even in middle and low income countries. And the good news, if there’s any reason for optimism, is these gene editing therapies. The one that KJ received is much more like the vaccines than it is like the bone marrow transplant. So it should be much more scalable, much more easy to deploy. I would hope the delay to get it from countries like the United States to many countries all across the world will be much shorter.
Rachel Jones/NPF (00:57:00):
Sharon Muzaki has such an important question that I’m going to give her the opportunity to ask the last question. Sharon, are you there? She may be having microphone problems as well. So let me ask it. Hello?
Sharon Muzaki | Nature Africa (00:57:18):
Oh,
Rachel Jones/NPF (00:57:18):
Hi.
Sharon Muzaki | Nature Africa (00:57:19):
Yes, thank you so much. My question is about how long, much trust time and emotionally labor that goes into preparing for families. I’m curious, how do we report around the, how do we misunderstand or overlook when reporting on these early conversations with parents, especially about their uncertainty and the month long consent process and the F ethical weight as you described, and how can we better capture that with a sense without centralizing science or oversimplifying the risks,
Simon Spichak | Being Patient (00:58:03):
But by 2030?
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (00:58:04):
That is a great question and I think that it’s one that I’ve thought a lot about as I’ve watched the coverage of everything that has happened this year, and a lot of reporters did a beautiful job. I’m not criticizing this, but until you’ve lived it as a member or as a team member trying to do this, you don’t fully appreciate how hard it is to communicate that part of the story, both for those of us who lived it, but also for the journalists who are trying to report it. Obviously people have length restrictions on their columns or on their stories, and I think that we are all sort of from pop culture. If you think about how Popp culture portrays novel medical breakthroughs or therapies, it’s often people work in the lab and then magically you cure a patient. And that’s not the reality of how science works, and it’s not the reality of how a process of trying to partner with a family around informed consent works either.
(00:59:02):
And so I can say, I think even thinking about this question about addressing the informed consent process, the uncertainty, the fact that we are not calling this a cure, that this is something we are learning from and we’re optimistic, but not making definitive claims when the claims should not be made or not ready to be made yet. I think all of those things will help journalists provide the information in a fair way, in an appropriate way to the public. And so I think even thinking about this question tells me that as you go forward to write this type of story, you’re going to be thoughtful about it. So having that thought process and that check in your mind of, okay, what was the true story behind the process? What was the actual discussions around safety, around the hard decision to do this for your child? I think having that sort of internal monologue as you write your stories or as you prepare your stories will go a long way. And just knowing that those shades of gray exist and it’s not all black and white, it’s not all baby cured, it is, we are trying to advance science to help a population of kids knowing that there’s a ton of uncertainty and a ton of risk involved. And I think trying to capture that gray area is really important.
Rachel Jones/NPF (01:00:21):
Well, that is my last question for both of you. How have you handled this fire hose of attention and interview requests? How has it been for the both of you, Karen?
Kiran Musunuru/Children’s Hospital of Philly (01:00:37):
It’s, it’s been intense. It goes in waves immediately around the time. In May when we made the first announcement about baby kj, there was intense press interest. And so we spent full days, morning till evening doing interviews, and then there were milestones that can’t come after that. For example, KJ going home, which happened several weeks after the story first broke. There was a wave of attention and interview requests. And even though the pace has settled down somewhat, I would say that we’re still doing at least several interviews a week related to KJ in one way or the other. And so it’s keeping us busy, let’s just put it that way.
Rachel Jones/NPF (01:01:17):
Well, I just noticed that. I think that’s Cookie monster behind your shoulder over here.
Kiran Musunuru/Children’s Hospital of Philly (01:01:23):
That’s Cookie Monster. Yes, indeed.
Rachel Jones/NPF (01:01:25):
So I hope that both of you are balancing the intensity with some levity, with some spa days, whatever. But I just want to reiterate how incredibly privileged we’ve been to hear from Kiran Musunuru and Rebecca Ahrens-Nicklas of Children’s Hospital of Philadelphia and the University of Pennsylvania. Thank you so much for providing us with the context to move ahead in this goal of reporting on rare diseases and children and families. So thank you both for being with us today.
Kiran Musunuru/Children’s Hospital of Philly (01:02:05):
Our pleasure. Thank you for having us.
Rebecca Ahrens-Nicklas/Children’s Hospital of Philly (01:02:07):
Thank you.
