At first glance, KJ appears to be a healthy, happy baby, but just months ago, his diagnosis of a severe metabolic disorder had his parents afraid for his life. Thanks to a multidisciplinary team of scientists spanning industry and academia, KJ received a gene therapy that was custom-made to treat his disease, and he is now thriving.
This remarkable milestone, reported in a study published recently in the New England Journal of Medicine, made headlines for being the first ever on-demand gene therapy to treat an infant with a genetic disorder.1 However, this breakthrough would have been impossible without a synergistic collaboration between multiple teams of expert scientists, working together to get the job done in a mere six months—a timeline unheard of in the world of gene therapy.
50 percent of infants with CPS1 deficiency will die, but a personalized gene therapy has saved KJ’s life.
Children’s Hospital of Philadelphia
Shortly after birth, KJ was diagnosed with severe carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an ultrarare disease affecting 1 in 1,300,000 people.2 “CPS1 is one of the first enzymes in the [urea cycle] pathway, so if you don't have any functioning CPS1, you can't clear ammonia,” said Petros Giannikopoulos, a physician and molecular pathologist at the Innovative Genomics Institute (IGI) and coauthor of the study. The resulting toxicity and brain damage cause death in about 50 percent of cases.
Giannikopoulos is part of the somatic cell gene editing consortium, an NIH initiative that meets in person twice a year. It was during one of these meetings in the fall of 2024 that he first heard his colleague Fyodor Urnov, a geneticist and vocal champion of gene therapies for ultra-rare diseases, and Kiran Musunuru, a physician who studies the genetics of cardiovascular and metabolic diseases at the University of Pennsylvania Perelman School of Medicine, discuss KJ’s case. They wanted to try to correct his unique genetic mutation in vivo using a derivative of CRISPR-Cas9 gene editing technology called base editing.
It would certainly be a challenge. KJ’s mutation had never been identified before, so they had to carefully design a therapy that was tailored just for him. They would also be racing against the clock to treat KJ before his disease caused significant and irreparable damage, and they would need to team up with experts and industry leaders across several fields to produce the medicine on a short timeline.
But if they didn’t try, KJ had a 50 percent chance of dying before he received a liver transplant, which is one of the only options available for CPS1 deficiency patients. Urnov, Musunuru, and Giannikopoulos decided to forge ahead, teaming up with physicians from the Children’s Hospital of Philadelphia. One of the key questions was how they would produce the therapy and get it approved in time.
Thanks to Urnov, the IGI already had a partnership with Danaher Corporation. “A few years ago, Danaher recognized that they had a lot of potential synergies across their [subsidiaries],” said Giannikopolous.
Those subsidiaries—Integrated DNA Technologies and Aldevron—prioritized KJ’s case and provided the various components needed to create the therapy in record time, such as the mRNA encoding the base editor and the guide RNA. Meanwhile, Acuitas Therapeutics generated the liver-targeting lipid nanoparticle to package them in.
Unlike traditional CRISPR, base editing does not create double-stranded breaks in DNA but instead uses bacterial enzymes to substitute specific residues, directed to the target site using a disabled CRISPR enzyme and a guide RNA. “In principle, base editors are supposed to be safer, but really the primary driver of this was just the feasibility of being able to package everything in a single lipid nanoparticle,” Giannikopoulos explained.
Giannikopolous and his team explored the on-target editing outcomes of correcting the mutation in depth, as well as any potential unintended genomic alterations. With a necessary level of obsession, they mapped out all the possibilities and selected the best approach.
Giannikopoulos said there was no room for ego in the broader team. “In great sports teams, there's this wonderful ethos that nobody cares who gets credit. It's just about winning a championship,” he remarked. “So, there was a feeling that there's a child's life on the line, let’s just get this done.”
Just six months after those first discussions, after preclinical testing in animals and an FDA fast-track designation, KJ received his first dose of the therapy. They took a cautious approach; KJ’s nonsense mutation caused a premature stop codon in the CPS1 gene, so his liver and immune system had never been exposed to the CPS1 enzyme before. “If you are now going to enable hepatocytes to make CPS1, there was some concern that maybe there might be sort of immune reaction,” Giannikopoulos said.
Fortunately, careful monitoring of KJ’s liver enzymes showed no signs of inflammation, and he was responding well. A month later, KJ received a second, higher dose, and he has since received a final dose. Now approaching his first birthday, KJ can consume a normal amount of protein and requires fewer medications than other people with CPS1 deficiency use to tamp down their ammonia levels.
According to Giannikopoulos, who has a background in oncology, the risks associated with gene therapy need to be reframed. “In cancer, we tolerate insane levels of toxicity, even in babies, in an effort to clear them of their cancer,” he said. “My explanation for why our risk tolerance in [gene therapy] is so much lower is that we don't think of people who have a genetic disease as being sick, in the sense that that's just who they are, because they were born that way.”
Recent guidance documents published by the FDA allow for CRISPR-based biologics to be assessed in umbrella trials, a platform-based approach in which a broader patient population would be treated under a single IND application, but with slightly different interventional arms depending on their mutation. “The idea is that you would, you would do a lot of the intensive safety and efficacy work for the first arm, and then once you get that green light, the idea is that you could then just tweak the program a little bit [for the others].”
Giannikopoulos is hopeful that with these changes, gene therapies will save more lives like KJ’s. “What this case really represents, to me, is the birth of the interventional arm of medical genetics,” he said.
- Musunuru K, et al. Patient-specific in vivo gene editing to treat a rare genetic disease. N Engl J Med. 0(0).
- Noori M, et al. Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review.Mol Genet Metab Rep. 2024;41:101156.
