Leaders of the gene-editing field join forces to develop and administer the first on-demand CRISPR therapy for an infant with a rare metabolic disease.
Since the development of CRISPR gene editing, leaders in the field have foreseen a future in which CRISPR could be used to repair any genetic disease — including rare “N-of-1” diseases caused by mutations that medicine has never encountered. A new paper published May 15, 2025 in the New England Journal of Medicine takes a big step toward making the vision of an on-demand CRISPR cure a reality. The article is titled “Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.” A team of physicians and scientists including five researchers from the Innovative Genomics Institute (IGI) at the University of California, Berkeley, achieved a historic milestone for the field: a personalized in vivo CRISPR therapy for an infant was developed and delivered to the patient in just six months. The patient, KJ, was born with a rare, severe genetic disease that affects just 1 in 1.3 million newborns. This landmark case paves the way for a future with on-demand gene-editing therapies for individuals with rare, until-now untreatable genetic diseases. “This was a remarkable team effort,” says Jennifer Doudna, founder of the IGI and recipient of the 2020 Nobel Prize in Chemistry for her role in the development of CRISPR gene editing. “The ability to develop an on-demand CRISPR therapy in such a short time opens up a new era for treating previously untreatable genetic diseases.”
KJ was born with a genetic mutation causing a CPS1 (carbamoyl phosphate synthetase 1) deficiency, an ultra-rare disease of the urea cycle that prevented him from being able to break down proteins in food. This disease has a 50 percent mortality rate in infancy; staying alive meant living in the hospital under constant monitoring. Powerful nitrogen-scavenging drugs and a protein-restricted diet were required to prevent toxic levels of ammonia building up in his body. At just 5 months old, he was placed on the liver transplant list. But when he was just over 6 months old, KJ received the first dose of his customized gene-editing therapy. Early results show no adverse effects, improved symptoms, and a decreased dependence on medications. KJ is now growing well and thriving. His parents are looking forward to bringing him home soon.
KJ was treated by a team of physician-scientists at Children’s Hospital of Philadelphia (CHOP) and Penn Medicine led by Rebecca Ahrens-Nicklas and Kiran Musunuru, who also led the work on engineering the gene editor. The research team at the IGI included Fyodor Urnov, IGI Director of Technology & Translation and Professor of Molecular Therapeutics at UC Berkeley, Petros Giannikopoulos, Director of the IGI’s Interventional Genomics Unit and Assistant Adjunct Professor of Laboratory Medicine at UC San Francisco, and IGI researchers Taylor Hudson, Kevin Briseno, and Aysel Ogul. Other collaborators on the team included scientists at the Jackson Laboratory, Aldevron and Integrated DNA Technologies (both operating companies of Danaher Corporation), and Acuitas Therapeutics. The multi-institutional group collaborated to design, test, manufacture, and coordinate regulatory review by the US Food and Drug Administration (FDA), so that the therapy could be delivered as quickly as possible.
Racing Against the Clock
Under normal circumstances, developing and testing a new CRISPR therapy takes years, but this patient — and others born every day with severe genetic disorders — do not have years to wait. Getting all of the pieces together for this emergency need took rapid coordination amongst teams at multiple academic and for-profit organizations, only possible because of both years of preparation and some lucky connections.
Developing CRISPR cures for rare disease has been part of the IGI’s mission since the institute was founded in 2015. Over the past two years, the IGI-Danaher Beacon for CRISPR Cures project has been developing a “cookbook” for designing and manufacturing on-demand CRISPR cures. Alongside this, IGI labs have been developing platform approaches to treating diseases with CRISPR as well as safety assays for gene-editing therapies, funded by the NIH’s Somatic Cell Genome Editing program. This same NIH program connected the IGI researchers with the team at CHOP and the University of Pennsylvania, including study lead Rebecca Ahrens-Nicklas.
In early August 2024, Musunuru and Ahrens-Niklas told Urnov the story of a clinical journey of a patient at CHOP suffering from a urea cycle disorder for which there was a clear genetic cause but no available cure, a story that motivated Urnov in IGI’s Beacon for CRISPR Cures project.
“My first thought was this is what we’ve been preparing for our entire lives,” says Urnov. “When our colleagues at CHOP and Penn told me about a newborn with a mutation causing a urea cycle disorder, I called our partners at Danaher and said, ‘We have to do this.’”
The lead Danaher scientist on the Beacon project, Sadik Kassim, replied immediately. Later, when the team needed a bespoke mouse model, the lead scientist at the Jackson Laboratory replied in less than 15 minutes.
“Everyone who was part of it sprang into action as if they were firefighters sliding down the pole,” says Urnov.
Prior to receiving the CRISPR therapy, KJ’s prognosis was poor, but there were several factors that made KJ’s case a good candidate for a rapid CRISPR intervention. An ongoing research study at the IGI called INGENUITI enabled the team to immediately enroll KJ and his parents for genome sequencing and analysis. The mutation in KJ’s genome was a single base — just a one-letter change in his genetic code — and one that could be corrected using base editing, a gene-editing technique that only makes a single-letter edit. Additionally, the researchers needed to edit cells in the liver, where the faulty protein is made. The liver is currently one of the organs in the body that can be targeted for in vivo gene-editing therapies using lipid nanoparticles.
Many things had to happen quickly. The team screened for an optimized base editor for KJ’s gene variant, encoded the optimized therapy in RNA molecules in lipid nanoparticles, established the efficacy of the therapy in a laboratory model, verified safety in a toxicology study, and performed a patient-specific off-target analysis to ensure that the gene editors posed little risk of unintended edits. The team also had to be able to manufacture the therapeutic molecules at a clinical grade. Clinical-grade manufacturing has been a hurdle for the field, a key reason that the IGI has been working with Danaher and their operating companies to streamline this process.
IGI researchers played an important role in optimizing the safety of the gene-editing approach and providing the data that enabled the FDA to allow the patient to be treated so quickly.
One of the first steps involved characterizing the mutation in KJ’s genome and designing the guide RNAs that allow the base editor to precisely target a specific letter in the patient’s genome for repair. Kiran Musunuru’s team at Penn accomplished that in record time. Next, the team at the IGI jumped in to do the necessary safety assessment work so that the FDA could assess the risks.
“Because of the INGENUITI research project, we were able to get access to the whole genome sequence the next day,” says Taylor Hudson, a PhD student on the IGI assay development team. This also enabled the team to use KJ and his father’s DNA instead of a general reference genome, making the gene-editor design and safety analysis more accurate.
The team worked on an assay called CHANGE-seq-BE that looks for potential off-target effects of the base editor anywhere else in the genome. Kevin Briseno, a research associate at the IGI, and Aysel Ogul, an undergraduate research assistant, focused on the lab work, while Hudson worked on the bioinformatics and computational analysis.
“It is a pretty involved assay. It takes about two weeks to complete just on the bench,” says Briseno. “We felt a lot of pressure to get this right on the first shot, because any sort of troubleshooting could set us back weeks, and with a patient waiting we couldn’t afford to waste any time.”
Hudson also says she felt the gravity of the situation. “We were always thinking, ‘I hope they’re doing good today.’ We thought about the parents a lot. That’s something I couldn’t imagine going through.”
The team’s focus (as well as their willingness to work through the holiday season of 2024) paid off, and the assay was successful. This was followed by an assessment of whether any possible off-target effects were potentially harmful or benign, and validation of these findings in the lab, all of which are needed by the FDA to evaluate the risk-reward ratio. In the end, the therapy was approved in just one week.
“This is a landmark moment for CRISPR in medicine, and we can never look back,” says Urnov. “A remarkable multi-institution team — CHOP, Penn, IGI/UC Berkeley, IDT, Aldevron, Jackson Laboratory — came together to show that one can create a CRISPR on-demand therapy in 6 months. It can be done even faster. Now we have to show that we can scale this from CRISPR for one to CRISPR for all.”
The discovery of CRISPR gene editing grew out of publicly funded fundamental research at UC Berkeley where Doudna and colleagues were investigating the mechanism of a bacterial immune system against viruses. The continued development of CRISPR technology at UC Berkeley and other global institutions has led to advances in medicine and sustainable agriculture around the world. Doudna founded the IGI to help ensure that CRISPR technology would be accessible to the people who need it most.
“I’m thrilled for KJ and his family, and I hope to see many more families benefit from this in the future,” says Doudna.
As of April 2025, KJ had received three doses of the therapy with no serious side effects, and is tolerating increased protein and needing less nitrogen-scavenger medication. He has also recovered from typical childhood respiratory infections without a dangerous build-up of ammonia in his body.