Rakiya A. Muhammad
In 2025, doctors corrected a life-threatening genetic disorder in an infant using gene therapy, marking a medical breakthrough.
From birth, baby KJ Muldoon faced CPS1 deficiency, a rare liver disorder caused by a lack of the enzyme carbamoyl phosphate synthetase 1 (CPS1). This enzyme is essential for removing ammonia, a waste product from protein breakdown. Without CPS1, ammonia levels in the body can become dangerous, requiring immediate intervention.
The scientists, Rebecca Ahrens-Nicklas and Kiran Musunuru, with the Innovative Genomics Institute, pioneered the CRISPR gene-editing therapy—a method for making precise changes to DNA—that enabled targeted correction of KJ’s DNA.
The landmark achievement was featured at the 2025 Rare Disease Reporting Fellowship, where experts detailed KJ’s case and discussed the broader significance of the therapeutic advance.
Addressing journalists from 29 countries, the doctors presented KJ’s therapy as a milestone offering new hope for the treatment of rare diseases.
CPSI Deficiency: Unravelling a Rare Genetic Puzzle
Kiran Musunuru, Professor of Translational Medicine at the University of Pennsylvania, explained that KJ’s case was especially dire because his liver lacked an essential enzyme, which is necessary for protein processing.
He added that inheriting two faulty gene copies, as in KJ’s diagnoses, results in no enzyme activity, leading to ammonia buildup and severe disease.
“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,” Musunuru stated.
If you make 50% of the enzyme, that is enough to clear ammonia and remain healthy, the gene editor explained.
The only way for someone like AJ to get this disease is by inheriting two defective copies—one from each parent, he pointed.
“Now you have 0% working protein, and that’s when you get into trouble because then you can’t do anything with the ammonia,” he added.
“It builds up in the body and is very toxic and causes a very bad disease.”
CRISPR: From Ancient Defender to Modern Marvel
Musunuru highlighted that CRISPR, a natural system bacteria use to cut viral DNA, now allows scientists to precisely edit human genes.
He described how bacteria evolved CRISPR to fight viral threats, drawing a parallel to how humans combat pathogens.
“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 the microscopic bacteria deal with the same sort of threats just on a different level,” he highlighted.
“In their world, viruses are the big threat. And so, they have evolved ways to help them. If they see a virus for the first time, they can’t do much about it. They either survive it or not.”
Musunuru expounded: “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, the bacterium can use CRISPR to actually search out and destroy that invader., And so that’s how CRISPR developed as an immune system.”
The gene editor elaborated on how scientists harness this system, comparing the human genome to a textbook.: Think of each chromosome as a chapter, and each gene as a paragraph. If there’s a typo—like a misspelling—CRISPR can precisely correct that single letter, restoring proper function.
“And in K J’s case, he had one of these misspellings, actually two misspellings in both copies of a particular gene.”
He noted that advances in CRISPR technology have led to more precise DNA editing.
Base editing, or Version 2.0 of CRISPR, he explained, enables scientists to correct genetic mutations by changing a single DNA letter rather than cutting the entire strand.
“Out of the 6 billion letters in that entire textbook, we can find just the one letter that needs to be changed and corrected; we have that degree of precision,” he asserted.
“That’s what we ultimately used in KJ’s case.”
Engaging Parents: Transforming Hope into True Partnership
Rebecca Ahrens-Nicklas, Assistant Professor of Paediatrics at the Children’s Hospital of Philadelphia and the University of Pennsylvania, described how KJ’s parents actively participated by asking questions and becoming true research partners.
“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 it means for the greater urea cycle disorder community and the greater rare disease community?”
“In that first conversation, they agreed that we should keep going with the scientific research, and from that moment on, we’ve been partners in all of this. So, I would give them regular science updates and research updates. “
The paediatrician emphasised the importance of clear communication and educating families about the disorder and therapies, describing this as especially rewarding.
She said, “The part of my job I love most is helping families understand their diagnosis and available therapies.”
Treatment Timeline: Mapping the Journey
Ahrens-Nicklas provided a concise overview of KJ’s treatment from the first dose to discharge, highlighting the remarkable advances in the care pathway.
“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,” she detailed.
“Kids with this disease, one way you help treat them is by restricting 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.”
The paediatric geneticist added that they had hints that something might be helping him very quickly, and that he subsequently received two doses over the next couple of months.
Baby KJ was discharged home at about 300 days old, while the medical experts continued to follow him closely.
“Throughout this process, we continue to see signs that he has benefited from the therapy,” Ahrens-Nicklas observed.
How Enduring is Gene Therapy? Unpacking the Longevity
The researchers said early signs are promising. “We anticipate durable genomic change, and time will tell in humans,” Ahrens-Nicklas remarked.
“But in animal models, we see that that correction is there, right? It changed the genome; it changed the patient’s DNA.”
Musunuru also expressed confidence that the genetic edit will remain stable and durable as the child grows.
“I would say pretty confident. It’s hard at this point to be a hundred per cent confident since we’re in very early days,” he stated.
“There are, 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.”
The professor gave 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.”
Musunuru, who participated in helping to develop some of the therapies for heart disease, asserted: “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.”
He added that once they’re down, levels remain low for a 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 one-and-done. Once you have the effect at the DNA level, even though the liver is still growing or at least turning over some cells, those cells eventually die off, “he accentuated.
“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.”
Opening Doors: Expanding Patient Access
Ahrens-Nicklas assured that efforts are underway to broaden access through clinical trials, so more patients can benefit from this historic therapy.
“You need formal trials where you essentially assess multiple versions of this drug; essentially the same drug that’s just tuned to an individual’s genetic variant,” she illuminated.
“Whether it’s patient A, patient B, or 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.”
The physician disclosed that some of the diseases for which people have inquired about the drugs for their children or their patients require correcting organs other than the liver.
Currently, the delivery system works only for liver disorders. Hundreds of inquiries have shown a huge unmet need, she noted.
“And so, we cannot do 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,” said Ahrens-Nicklas.
“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.”
She believes that, eventually, it may be cheaper than procedures such as liver transplants, and that funding and insurance reimbursement are critical for widespread adoption.
“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,” she pointed out.
“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.”
Global Gaps: Bridging Disparities with One-Time Remedy
Ahrens-Nicklas observed that access to care for patients with rare diseases differs from country to country.
She cited KJ’s case, noting that without gene editing, he would have required a special metabolic formula, dialysis and later 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,” she highlighted.
“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.”
The physician added, “Liver transplantation is similarly not available everywhere. And so, if we could develop a process by which one could deploy a one-and-done therapy.”
“It would keep a patient safe without having to undergo a 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.”
Ahrens-Nicklas revealed how they envision expanding access worldwide. “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,” she said.
“It uses techniques that have already been developed for a variety of other uses and deployed throughout the world, including developing nations.”
“So, the same sort of technology to make that soap bubble, to put the cargo inside that soap bubble, that’s appropriate, has 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.”
Ahrens-Nicklas argued that repurposing local manufacturing sites for drug development, or enabling patients to travel to a centre before returning home, could better meet the needs of patients with rare diseases worldwide.
“So, I worry about access all the time. I worry about access within the United States. I worried about access around the world, “she revealed.
“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.”
