How Scientists Made The First Gene-Editing Treatment For A Baby

FLORA LICHTMAN: Hey, this is Flora Lichtman, and you’re listening to Science Friday.

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Today on the podcast, the story of a medical breakthrough many years in the making.

REBECCA AHRENS-NICKLAS: One of my biggest fears in this whole process has been giving false hope. And so I wanted to be honest about all the things that could go wrong.

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FLORA LICHTMAN: Last month, an historic first. Scientists created the first personalized, gene-edited treatment for a baby who was born with a rare, life-threatening genetic disorder. After three doses, the baby’s health significantly improved.

So how does this gene editing treatment work? What are the risks? And what does this breakthrough mean for the 30 million people in the US who have a rare genetic disease with no available treatments?

To help get some answers, I’m joined by the physician scientist who led this research, Dr. Kiran Musunuru, Professor of Translational Research at the University of University of Pennsylvania, and Dr. Rebecca Ahrens-Nicklas, Assistant Professor of Pediatrics and Genetics at the Children’s Hospital of Philadelphia and the University of Pennsylvania. Welcome to you both to Science Friday.

KIRAN MUSUNURU: Thank you so much for having us.

REBECCA AHRENS-NICKLAS: Yeah. Thanks for having us.

FLORA LICHTMAN: Rebecca, let’s start with your patient, KJ. Tell us a little bit about him and how he became the first baby to get this treatment that you all developed.

REBECCA AHRENS-NICKLAS: Yeah. So KJ was born last summer, and unfortunately, within the first two days of life, he became quite sick. He had a very, very high level of a chemical in his blood called ammonia.

And so the ammonia was causing KJ to be very sleepy and not feed very well. And this is a huge medical emergency, because unless you can get rid of that ammonia, the baby is at risk of having permanent brain injury. And unfortunately, a high number of infants that are born with this type of disease die very early on in the neonatal period.

FLORA LICHTMAN: And do we know what was causing it? What was the illness?

REBECCA AHRENS-NICKLAS: Yeah. So the illness is something called a urea cycle disorder. So your urea cycle essentially helps you get rid of that ammonia. It helps you break down protein properly so you can get rid of that ammonia that can build up and be toxic.

And he has a specific genetic change that causes one step of his urea cycle to not work. In this case, it’s the step called CPS1. And so he has something called CPS1 deficiency. Essentially, all that means is he has a genetic change that converts his urea cycle into a nonfunctional cycle. So ammonia will build up whenever he is sick or whenever he eats too much protein.

FLORA LICHTMAN: Kiran, how did you come into this?

KIRAN MUSUNURU: So Rebecca and I had been working for several years, trying to figure out the best way to help patients like these very sick patients who have missing or broken enzymes in the liver that cause these conditions, urea cycle disorders. And we’ve been using a particular type of gene editing called CRISPR. Effectively, it can actually make changes to the genetic code, it can actually correct misspellings.

So we’ve been experimenting with using this technology to try to figure out how to correct misspellings. And so we’re able to fairly quickly craft a gene editing solution that was tailored just for KJ. Now this is very important, because many patients who have these particular diseases, they have a unique variant that they may not share with anyone else in the world.

FLORA LICHTMAN: Oh, wow.

KIRAN MUSUNURU: And so that was pretty much the case with KJ And so we had to make a bespoke editing solution just for him. So that was one challenging aspect of trying to do this for KJ. The other challenging aspect is he was very, very sick.

And even something as benign as a common cold that most of us would just shrug off could be life threatening for him. And it was clear this was going to continue happening. And if anything, it was going to get worse over time. And the only prospect of fixing this long term is a liver transplant. It’s a very crude way of replacing that broken enzyme, or that missing enzyme, by replacing the whole liver.

FLORA LICHTMAN: The whole liver. Yeah.

KIRAN MUSUNURU: Because the whole liver will have the proper enzyme. And the problem with that is it’s not 100% safe, and it’s particularly risky if you’re doing it in a very young child. And of course, sometimes there’s not a match available. And all that time, there’s risk of the ammonia levels rising with any little stressor and causing permanent damage to the brain, or even coma, or even death. So the clock was ticking. We had to do this quickly.

FLORA LICHTMAN: Well, that’s what I wanted to know. How quickly did you have to do it? What was your timeline?

REBECCA AHRENS-NICKLAS: Yeah. So we wanted to do it as quickly as we possibly could, but in a way that was still safe. And we often have to wait until an infant is big enough to have a liver transplant. And oftentimes, that takes it about the time until the baby turns one.

And so we thought that if we could come up with an editing solution before that first birthday, we would have the potential of maybe helping a baby like KJ. And so given the complexity of trying to do this for the first time, including manufacturing a drug, making sure that it was safe, making sure we had all the proper approvals from the Food and Drug Administration, that this would definitely take us eight months, nine months at least to get to that point.

And that was if everything went perfectly right. And so I set a very ambitious timeline, thinking that we would absolutely go over that timeline. And so I said, we need a drug in hand by the time he turns seven months old.

But I’m very happy to say that we actually got the approval from the Food and Drug Administration to administer this therapy a week ahead of schedule. So much of this story happened because so many people stepped up to help us. And everybody worked around the clock, nights, weekends, v putting everything else on hold to try to make that very aggressive timeline.

FLORA LICHTMAN: What were the conversations with KJ’s parents like? I mean, what were the risks and how did you talk them through it?

REBECCA AHRENS-NICKLAS: Yeah. They were remarkable, I will say. I had a very candid first conversation with the family. I essentially told them, I have no idea if this is going to work. I have no idea if we’re even going to really get to a point where we can manufacture a drug to even try for your child.

And I was honest also. I said, I have no idea. It could do harm. One of my biggest fears in this whole process has been giving false hope, and so I wanted to be honest about all the things that could go wrong, both in the development process, but also after dosing.

And so in that first conversation, they took it all in. They looked at me and said, we know that this might not work. We know that this might have no benefit for our child, but we think the science is important to advance, and we realize that this could have implications and benefits beyond our son. And so we fully support you working on this in a research capacity and to keep moving this forward.

In parallel, we continued the gold standard clinical care that any child with CPS1 deficiency would receive. And this included listing him for liver transplant, actually, at an early age, at about five months of age, because he was so severe. So the research efforts were going on in parallel with the clinical efforts, but they became full partners in this.

FLORA LICHTMAN: I mean, aside from false hope and that it wouldn’t work at all, what were the risks around dosing, or unintended consequences?

KIRAN MUSUNURU: So the way this treatment works is you have the two components of CRISPR. We wrap them up in what you can think of as soap bubbles, very, very, very tiny soap bubbles. And literally billions of these little soap bubbles all put together in this little solution that you end up putting into the body intravenously through an infusion over about two hours. And once this therapy hits the bloodstream, it very quickly gets taken up by the liver.

So the job of the liver is to clean things out of the blood. So pretty much anything you put into the blood will get taken up by the liver to some degree. So we’re able to take advantage of that in these little soap bubbles. They take the components of the gene editing therapy right into the liver cells.

And once there, they start to do their job and make the correction. And that actually is a pretty safe process. The biggest risk is there being an allergic reaction.

The other issue that can arise is that there’s actually a lot of stress on the liver. And so it can have some injury. And we were unsure exactly what to expect, because no treatment like this has ever been given to a child before, much less an infant.

It’s been given to adults, I’d say several hundred adults by now. And in general, it’s proven to be quite safe.

FLORA LICHTMAN: There’s clinical trials, right, for adult gene editing treatments?

KIRAN MUSUNURU: Exactly. There are several clinical trials underway. So that gives us some reassurance that it would probably be safe in a patient like KJ, but we didn’t know. And a baby is not simply a young adult. It can be a very, very different situation.

FLORA LICHTMAN: So for this to work, do you need every single cell in the liver to be changed?

REBECCA AHRENS-NICKLAS: I think it depends on the underlying disease that you’re trying to treat. For some rare diseases, and some common diseases, yes, you’re going to have to correct every cell in the liver. But for most of our metabolic disorders, we know that if you can correct a small fraction of the cells, that there should be a therapeutic benefit.

FLORA LICHTMAN: OK. And I know that there’s a GPS attached, and so presumably, they’re going to the right place to snip the right thing. But do they ever make mistakes? And is that a concern?

KIRAN MUSUNURU: So that is a possibility with this kind of technology. The gene editing technology can occasionally get fooled and go to the wrong place, and potentially make a change. Now this is something we’re obviously very, very, very careful about. And we did quite a lot of work beforehand to KJ to make sure that this kind of thing wouldn’t happen.

And so one interesting feature, I would say, about this particular case is that KJ underwent genetic testing immediately after birth, once it was clear he was sick, to try to identify the genetic change that was responsible for his disease. And that’s become quite routine over the last few years. But because of that, we actually had the entirety of his genome sequence.

And so we were able to actually use that information to analyze the GPS address that we were using in the treatment and make sure that for his individual genome, for his code, that it was unlikely that it was going to go anywhere other than where it should go.

FLORA LICHTMAN: How did KJ respond to the treatment?

REBECCA AHRENS-NICKLAS: Yeah. So we all watched him very, very carefully for the couple hours over which his first infusion ran. And while we were all very nervous, he actually slept through the entire thing. He did great.

FLORA LICHTMAN: And is it permanent or do you expect that KJ would get follow-up injections as he gets older?

REBECCA AHRENS-NICKLAS: It’s a great question. We don’t know, because this has never been given to a baby or an infant before, whether that change will be durable. We anticipate that it would, because if you make that correction of that specific genetic variant that’s misspelled, as the liver cells grow and divide, they will pass on that correction to the new liver cells.

And we know that going from a six-month-old baby to a full-grown adult, his liver is going to grow and divide a ton. So we anticipate that change will be passed on, but only time will tell. And so we will continue to watch him very carefully.

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FLORA LICHTMAN: After the break, can this approach be scaled from one baby to millions of patients with rare diseases?

REBECCA AHRENS-NICKLAS: If KJ is the only patient that is treated with this type of approach, then we failed in what we’re trying to do.

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FLORA LICHTMAN: We know that rare diseases often get overlooked by pharmaceutical companies because there’s no financial incentive. Where did the money come from to develop this?

KIRAN MUSUNURU: So the majority of the funding came from the United States National Institutes of Health, which is the biggest funder of biomedical research, not just in the country, but the world. But I would also say that we had a lot of academic and industry partners who came together to actually manufacture the drug and do the studies that needed to be done so that it would be acceptable from the perspective of the Food and Drug Administration, the FDA, to actually be able to give it to a patient like KJ.

And they just stepped up and volunteered on their own to contribute to this project. And so it’s very hard to say exactly how much the entire effort cost. But between the federal funding from the National Institutes of Health, the NIH, and the in-kind contributions from the companies, that was the vast majority of the support that made this possible.

FLORA LICHTMAN: I mean, we’re talking about a solution for one patient and a ton of resources marshaled for one patient. Is it possible to scale this, and what are the challenges that go along with that?

REBECCA AHRENS-NICKLAS: Yeah. I think it’s essential that we try to scale this. If KJ is the only patient that is treated with this type of approach, then we failed in what we’re trying to do. And so what we are really working to do is to move from personalized therapies to robust clinical trials, where you have groups of patients who might each have their own individual genetic variant, but you can then essentially develop a different version of a gene editing drug to treat a variety of patients, but in a formal, what we call platform trial.

And through those types of formal trials, we’ll be able to really measure whether or not these types of drugs work and whether or not they’re safe. And once you have those definitive clinical trials, these can become approved therapies. So what we’re really trying to do is build a platform approach with formal clinical trials to get these to become approved therapies.

FLORA LICHTMAN: So this came out of significant NIH investment over years. How are the cuts to the NIH affecting the future of your work, and, in your view, the future of developing other breakthrough medical treatments like this one?

KIRAN MUSUNURU: So I think the biggest problem right now is the uncertainty. So there have been cuts, and there have been grants that have been terminated, and it’s affected a lot of our colleagues. We’ve been fortunate in that nothing we are doing has been affected yet.

But if the budget is slashed, or what’s known as indirect funding, which is sort of extra funding that comes from the NIH to support infrastructure, if that gets scaled back, it will hurt what we are trying to do. There’s no doubt about it.

The infrastructure is very important. You need institutional support. You need a regulatory team. You need clinical trial infrastructure. You need a nursing staff who are trained to be able to administer experimental therapies to patients.

And so those are just a few examples of everything that needs to go into an effort like this one. And so the future of funding is absolutely critical to what we’re trying to do, and what we hope to do, and what we hope others will be able to do.

FLORA LICHTMAN: I mean, to me, as a layperson who covers this but is not a scientist, it really feels like a stunning discovery. What is it like for you all?

REBECCA AHRENS-NICKLAS: It has been one of the most emotional, challenging, and exciting years of my life, trying to get this program to move forward since KJ was born last summer. I’ll be honest. There have been points that I have been incredibly terrified.

It is amazing to have the opportunity to try to advance this transformational science into patients for the first time. But with that, I’ll be honest, there’s times where we were just scared that we didn’t know what the outcome would be. We didn’t know what the next 24 hours would bring. And so it has been a very exciting but very overwhelming process, I will be honest.

FLORA LICHTMAN: One more question for you all. How do you feel like the story has been covered in the press?

REBECCA AHRENS-NICKLAS: Yeah. I feel that the story has been covered well by a lot of really talented and well-meaning journalists. There’s been–

FLORA LICHTMAN: “Well-meaning.” Oh, no.

REBECCA AHRENS-NICKLAS: No, I don’t mean this in a bad way. I mean this in a good way. This is a complex approach to trying to treat a patient. There’s a lot of science. There’s a lot of medicine. There’s a lot of specifics about an ultra rare disease that no one has ever heard of.

I have to tell you, it has been amazing to hear in the popular press people talking about the urea cycle, which, as a metabolic geneticist, warms my heart that people can actually that cycle exists now. I think that in a story like this, where all of us want a perfect ending, I think it has been easy for some media outlets to jump to the conclusion that KJ is cured.

And we have been very careful to never use that word, because in reality, this is more of a treatment than a cure at this point in time. We think we made his incredibly severe urea cycle disorder less severe, but we still are caring for him on a regular basis and making sure that we keep him safe. So I think it’s really important, as we speak with the rare disease community, when we speak with other families, that everyone is aware that this is what I hope is a step in the right direction.

But we have to be honest about what we know and what we don’t know. And any time you treat a single patient, it’s really hard to make definitive conclusions about how well something worked or even how safe something is. And the only way we’re really going to know how well these therapies work is by doing larger trials in a formal clinical trial setting. And so that’s why we’re really trying to push towards that next step so that we can really understand, as a community, what these drugs are capable of doing.

FLORA LICHTMAN: I want to thank you both for this very thoughtful conversation.

REBECCA AHRENS-NICKLAS: Thank you.

KIRAN MUSUNURU: Thank you so much.

FLORA LICHTMAN: Dr. Kiran Musunuru, Professor for Translational Research at the University of Pennsylvania, and Dr. Rebecca Ahrens-Nicklas, Assistant Professor of Pediatrics and Genetics at the Children’s Hospital of Philadelphia and the University of Pennsylvania.

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Thanks for listening. Don’t forget to rate and review us if you like the show. And you can always leave us a comment on this segment on Spotify. We’d love to hear from you. Today’s episode was produced by Dee Peterschmidt. I’m Flora Lichtman. Thanks for listening.

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