The world’s first personalized gene therapy

Transcript

Sam Diamond: Hello, fellow science fans. Thank you for joining us At the Lab where we talk about inspiring curiosity, discovery, innovation, and the many ways that science makes life better. For Cold Spring Harbor Laboratory, I’m Sam Diamond, and today, we’re bringing you a discussion with the two physician-scientists responsible for the world’s first-ever personalized gene therapy: from the University of Pennsylvania Perelman School of Medicine, Dr. Kiran Musunuru, and from the Children’s Hospital of Philadelphia, Dr. Rebecca Ahrens-Nicklas.

SD: This discussion took place during Cold Spring Harbor’s annual Genome Engineering: CRISPR Frontiers meeting, and we touch on a host of topics from the science of gene editing to its clinical applications to the importance of collaborations and meetings like this one.

SD: Before we get into it, I’d like to invite you to subscribe to our podcast, and please remember to like and share your favorite episodes, because science is always better when explored together. Now, without further ado, here’s my talk with Kiran Musunu and Rebecca Ahrens-Nicklas.

SD: We’re here at the Genome Engineering: CRISPR Frontiers meeting, part of Cold Spring Harbor Laboratory’s Meetings & Courses Program. So, the first question I’d like to ask is what is CRISPR?

Kiran Musunuru: So CRISPR is an adaptive immune system that’s found in many bacterial species. It’s been there for billions of years. But the reason we’re excited about CRISPR now is that many very accomplished scientists over the years have been able to figure out how that CRISPR system and bacteria works and then unlock the ability to adapt it into a tool that can actually be applied to human health.

KM: So it came out of bacteria, but now it can be applied in human cells as a gene editor, which means we use it to make changes in a very controlled programmable way in the genome. And that can have implications for a whole variety of things: agriculture, for example, making foods that are more nutritious or more palatable; making animal models to better study diseases. But where a lot of the excitement with CRISPR gene editing is, is the application to human health, being able to treat patients with diseases that previously had no treatments or had great medical need.

SD: Rebecca, could you speak a little bit more to the clinical applications, how you became aware of this field, and its possibilties?

Rebecca Ahrens-Nicklas: Yeah, I mean we’re at a point now where it really can be applied in the clinic, which, as a physician-scientist, is incredibly exciting. So, I take care of lots of kids with rare genetic diseases, and you can essentially adapt the technology to help address lots of different genetic diseases and try to help lots of different patients. And so it really seems like the potential is limitless, albeit there’s still a lot more work to do. But it’s a really exciting time to think about personalized medicine, and CRISPR really made it possible.

SD: You said you treat kids with a lot of different genetic diseases. I’m curious on a personal level, what got you into pediatrics?

RA: Yeah, so it was a pretty obvious decision in all honesty. After my Ph.D. work, I was doing some of my clinical training. One of my first rotations was pediatrics. And I realized first off, I love working with kids, but secondly, if you’re interested in the molecular basis of disease or really moving from bench to bedside, so many pediatric diseases are genetic diseases. So, in a lot of ways, it was a very natural environment where physician-scientists could really try to make a difference.

SD: Kiran, same question to you: Why heart disease?

KM: Well, heart disease is the leading cause of death worldwide, bar none. Even in the poorest countries on earth, it has become the leading cause of death more than infectious diseases. It is the preeminent global health threat in the 21st century. And it doesn’t discriminate. We all know people who have been affected by heart disease, we’ve have family members, or we’ve had it ourselves. And so 18 million people a year worldwide succumb to heart disease. And so my thought was if I could change the trajectory of that disease, that can make it so that we could push off heart attacks and strokes by years, maybe even decades, that could have a big impact.

KM: If you’re talking about the leading cause of death, it could actually improve life expectancy. And unlike with genetic diseases where everyone has a different disease or maybe have different genetic variants causing those diseases, heart disease is basically a single entity. It’s about getting plaques in the arteries that feed the heart muscle and then them rupturing and causing blockages. That’s what causes a heart attack. If you could get the root cause of that disease, you could potentially come up with a one-size- fits-all solution that could help literally millions and millions of people. And so that’s how I got into gene editing as a therapeutic modality. The idea that I could use CRISPR gene editing to turn off cholesterol genes in the liver. You could give a single treatment. You could permanently reduce someone’s cholesterol levels, and that would offer them lifelong protection against heart disease.

KM: And so I was working on this for more than a decade before the clinical trials got underway, And it’s still early days, but they’ve shown success. There have been patients who have had that bad heart disease and have received the therapy in a clinical trial. And it’s worked exactly as we hoped. It’s reduced their bad cholesterol levels substantially, in some cases more than 60%. And that has proved to be durable so far out to two to three years

SD: Becca, you mentioned that you specialize in rare genetic diseases. So, what is CPS1 deficiency?

RA: So, CPS1 deficiency is what’s called a rare inborn error of metabolism. So, all that means is that a patient has a genetic difference or a genetic variant that disrupts a biochemical pathway in the body. In this case, it’s the urea cycle. And the urea cycle is really important for breaking down protein, specifically getting rid of the part of the protein that can become toxic, something called ammonia. So patients that have CCPs one deficiency can’t process protein in the typical way, and they’re at really high risk of having ammonia build up—this neurotoxic chemical—anytime that they eat too much protein or they get sick or if they don’t have proper medical management.

SD: Obviously, CPS1 deficiency is not a heart disease. So, how is it that you guys end up collaborating?

KM: Yeah, so we’d made enough progress with heart disease that I’d started to ask the question, around summer of 2021, starting to think about, OK, how can I build on this? What can I do beyond this to really take this same technology and help as many people as possible? And I was very open to the idea that a patient is a patient. In a sense as physicians, it doesn’t matter what disease they have; we want to help them. We want to make them feel better, help them live longer. And so that’s when I connected with Becca, and we started brainstorming about whether the technologies that I’ve been using to make these treatments for heart disease could be useful for her patients because a lot of the diseases that affect the patients whom she cares for, they’re centered in the liver.

KM: So I’m tackling heart disease by focusing on the liver, but that’s just how cholesterol works. And many other diseases, even though they have nothing to do with heart disease, it’s effectively the same strategy: Get the gene editor, get CRISPR into the liver, with one slight distinction. In my case, with heart disease, I was trying to turn off cholesterol genes. For Becca’s patients, the goal would be to actually in a sense take broken genes and fix them and turn them back on and be able to produce missing enzymes or broken enzymes in the liver that cause the conditions that affect Becca’s most severely affected patients.

RA: Around that time, my lab, which I had opened a couple of years earlier, has really focused on trying to correct metabolic diseases in the brain itself. But what’s great about this approach for disorders like urea cycle disorders is that the target organ that’s affected the most in these kids is the brain, right? It’s the buildup of something toxic because the liver isn’t working properly that causes neurologic injury. So even though we were targeting the liver, in the end, the goal really is to protect the brain and improve neurologic outcomes in these kids. So, it fit very nicely with what my group is doing.

SD: So, we’ve spoken a bit about rare diseases as a model for potentially treating other diseases, but I also, of course, want to hear the story about this collaboration, which led to the first-ever personalized gene editing therapy, famously delivered to Baby KJ, a child with CPS1 deficiency. Tell me the story of how your collaboration led to this breakthrough.

RA: Yeah, so as Kiran had said, we had started working together summer of 2021, thinking through what disorders or what diseases might be benefited by this type of approach when we think about metabolic diseases. And in all honesty, the first disorder we came up with and started working on was PKU or phenylketonuria. It’s a different metabolic disease, but the same idea where you can’t break down protein properly and at this point a different toxin builds up.

RA: It’s a relatively common rare disease, and we worked on this for a number of years and are still working on it in animal models and cell models, and realized after about a year and a half of work, that we really could edit and correct changes in the liver that causes disease in mice and have an incredible effect on the mouse, such that these mice who had very high phenylalanine levels, very similar to what my patients have in clinic, those levels would entirely normalize within 48 hours.

RA: And when we saw those data over and over again, I realized that we really needed to expand this to some other more rare and really ultra rare diseases where no one was thinking about trying to develop therapies and where there was a huge unmet need. And in this case, it’s really urea cycle disorders for me as a clinician, because these kids are some of the sickest that I care for, and they really don’t have a great option available to them. The goal is to have them grow big enough to get a liver transplant, essentially a very extreme form of gene editing. You put the entire urea cycle in the form of a new liver. But unfortunately, while kids are waiting to grow big enough, they often have permanent neurologic injury from this elevated ammonia. And so, they’re just not a good option for them.

RA: And so, when we saw PKU data coming in, Kiran and I decided that we needed to expand our efforts and start working on urea cycle disorders. Really, from there, we just worked nonstop to try to get to a point where we could a develop therapy for a urea cycle disorder.

SD: And the clinical application speaks for itself at this point, right?

RA: Yeah, so I think that as the physician that was responsible for actually giving this drug to a patient, I had two big concerns. One is I didn’t want to give the family false hope, and to this day, I’m very honest to them and say, we don’t know exactly. This is new, this is research. At the very beginning, I would say, this could do harm to your child. This might do nothing. We might not get to a point where we make a drug for your child. There were so many things that could have gone wrong.

RA: And to this day, we still tell them he still has a urea cycle disorder. He still is under the care of our team at CHOP. Hopefully, and I think, we have made his very severe urea cycle disorder less severe. And importantly—knock on wood, everywhere—there weren’t any serious adverse events. So, it seems like it was really well tolerated and safe, but this is still an ongoing clinical research experience. And so, I think we all have to be honest about what we know and what we don’t know. And I will say the family is incredibly brave for partnering with us on this and really going on this crazy roller-coaster of the past year as we’ve tried to work with them to really help provide the best care we can for their son.

SD: What are the implications here in your eyes for future treatments and maybe for public health in general?

RA: Yeah, I think that this technology has great potential, and I think that this experience that we’ve tried to demonstrate shows that it is possible to move from the lab into a first in human therapy very quickly in a timeframe that might actually help one of these sick babies or an individual with a different genetic disease. I think it’s also really important to be forthcoming about a number of things. First, in order for this to happen, everyone essentially that worked on it had to drop everything and worked really, really hard and donate their time, donate their effort, and really the stars aligned because everyone was driven by the common mission of trying to help this baby. But that’s not a sustainable model if I’m going to try to treat the other patients in my practice or the other patients that exist in the world with rare diseases.

RA: And so, we really need to come up with sustainable models to be able to design, implement, test, and then eventually prescribe these novel gene editing therapies. It really has to be formal platform clinical trials, so that we can eventually get approvals of these medications as drugs. We cannot do these n-of-1 compassionate use experiences over and over and over again because it’s just not sustainable; the resources don’t exist for that.

RA: The other thing we need to be transparent about, and this is a conversation I have with rare disease patients all the time right now, is that this technology is not ready for every disease. I hope it will be. And I think there’s been a lot of exciting data shown here about how these technologies are going to be adopted to different types of genetic variants, to different organ systems. But it’s really important to know where we are right now and what’s clinically feasible, because we have had hundreds, thousands of requests from patients who are asking for help, understandably. And unfortunately for many of the diseases that I care for, and in many rare diseases, correcting the liver isn’t enough.

RA: And so, I think that it is a very exciting moment in genetic medicines. I think hopefully this example has sort of made people excited about the possibility of advancing these technologies, but we still have a lot of work to do before this becomes applicable to many rare diseases or most rare diseases. I think we’ll get there, and I’m excited about it. It’s a really cool time to be a clinical geneticist, but I think we still have a lot of work to do over the next coming years.

SD: Changing tracks a little bit, Kiran, you said you’ve been here many times before. Could you tell us a little bit about your experiences with CSHL Meetings & Courses over the years?

KM: I’ve been coming here for many, many years. I first came here when I was a graduate student to meetings here. It’s very different as a graduate student, I have to say, than as a professor, as a faculty member with a lab of my own and now bringing a whole bunch of my trainees to the meeting. It hits a little bit differently, but you still feel like you’re part of this grand tradition that goes back decades. You can’t help but see it because you see the pictures on the walls of these near legendary people that you read about in books and you learn about in grade school. You see these pictures, and then you realize, wow, they’re human beings. They’re people, not all that different from us, and we’re just part of a grand tradition that continues on.

KM: And the progress that has been made since some of those pictures from the 1950s is absolutely astounding. And so, it was fun coming as a graduate student and meeting the big names in the field. And I remember being very excited. For example, this was long before Jennifer Doudna became world famous for her innovations in CRISPR and getting a Nobel Prize, but she started and still is an RNA biologist. And my Ph.D. thesis was in RNA biology, so I came to a meeting on RNA biology, and I just remember being so thrilled and excited when I was presenting my poster and Jennifer Donna came by and actually started talking to me about my work and leading her through the program.

KM: For me, that was a pivotal moment that I’ll never forget that just even [after] many years, decades, resonates with me. And so, the feeling now that I’m grown up and now I’m one of those senior people and this year a co-organizer of this particular conference and being able to meet and hopefully inspire a lot of trainees in turn, I think that’s a very special feeling.

SD: Yeah, one of the great benefits of working here actually is I can just go to these meetings and hang out, get to meet scientists like yourselves. So, I’m curious to hear a little bit about that intersection between education and research and also just the importance of collaborations like yours for the future of science and medicine.

RA: I mean collaboration is essential. There’s no way that any one person or one group of people could have done what we have done in the past number of years. And I think that’s true for most major scientific advances, especially in today’s quickly changing world, there’s so much great technology, so many great applications of that technology. You need people who are well versed and can bring their expertise to the table. And if we don’t come together to do that, there’s no point in doing any of this.

KM: Yeah, just not to put too fine point on it, but Becca and I, for better or for worse, have become sort of the figureheads of this entire project, but it involves so many people, including some of our peer scientists who are here at this meeting. And so it’s nice to see them and discuss and build on the previous collaborations along the lines of what ultimately led to this treatment for Baby KJ, but laying the seeds for future collaborations.

KM: I’ve been struck just over the last couple of days here at this conference [by] some of the new work that’s being presented, and the wheels are spinning. It’s like, wow, that fancy new technology I can imagine how that might potentially help a whole new group of patients. We can make a whole new class of treatments. And just getting excited and thinking about that and chatting with the person who presented that work and brainstorming and thinking, how could we put this into practical use? And that’s happened to me several times already. I’m sure more will happen in the next couple of days. To me, that’s the real value of the networking that can happen at a conference like this.

SD: Well, with that, I don’t want to take away too much more of your time from the event. Let me just say that this has been an absolute pleasure. And thank you both so much for sitting down to speak with us. We really appreciate it, and we hope you enjoy the rest of the meeting.

RA: Thanks for doing this.

KM: This was great, sure, a pleasure.

SD: As this discussion illustrates, science is a shared, collaborative story. Discovery and innovation come from the curiosity inherent in each of us. Thank you for supporting science by listening and learning right alongside us. If you’re interested in more news about Cold Spring Harbor Laboratory research and events, subscribe to this podcast, sign up for our newsletter, and follow us on social media so you can share with us how science impacts you. To support research, education, and collaborations at Cold Spring Harbor Lab, please consider making a tax-deductible donation online at give.cshl.edu. Because science makes life better.