Scientists have corrected an extremely rare and life-threatening genetic disease of the liver in mouse models and human patient cells, using the gene-editing approach that served as the basis for the historic, life-saving treatment of Baby KJ Muldoon in 2025.
Led by scientists from the Rare Disease Translational Center (RDTC) at The Jackson Laboratory (JAX), the Broad Institute, and the University of Southern California, the research lays the foundation for a potential new therapy for Zellweger spectrum disorder (ZSD), an incurable disease that affects 1 in 50,000 to 90,000 births in North America.
The findings appear today in Nature Biomedical Engineering .
“This is about more than correcting a single mutation,” said RDTC Vice President Cathleen (Cat) Lutz, a co-senior author of the study. “It’s about building a new paradigm for how we develop genetic therapies, one that starts with precise disease models, scales through platform technologies like base editing, and ultimately reaches patients faster.”
A genetic disorder with deep implications for the liver and central nervous system, ZSD is caused by mutations in PEX genes that make cell structures called peroxisomes, structures that break down fats and remove toxins. When peroxisomes don’t function properly, the liver, brain, and other organs can become damaged.
The team showed that base editing, which corrects individual DNA letters without cutting DNA, can repair mutations in the PEX1 gene that causes ZSD. The study demonstrated that this edit restored function of the liver and peroxisomes when made in mice and patient-derived cells modeling the disorder.
The scientists also showed that the efficiency of the base editors increased over the duration of the study. A lower dose of base editors was able to achieve the same level of editing over time as the higher dose tested by the team.
“We are really excited about the possibility of using this tool that can correct a genetic error. If we can do that in patients, doctors won’t only treat symptoms like they do today. Moving these therapeutics to the clinic means we will be fixing the underlying problem with a permanent treatment,” said Maximiliano Presa, a lead scientist at JAX’s RDTC who co-led the work.
Advancing therapeutic technologies
The breakthrough builds on a long-standing collaboration led by Cat Lutz alongside David Liu, a Core Member of the Broad Institute, and Joseph G. Hacia, a medical geneticist from the Keck School of Medicine of the University of Southern California.
“I am honored to collaborate with the outstanding teams led by David Liu at the Broad Institute and Cat Lutz at The Jackson Laboratory on this work,” said Hacia, a co-senior study author. “There is a critical unmet need for therapies that address the root causes of genetic disease. Our findings in a common form of ZSD point to a potential path forward that may extend to other conditions, and we look forward to continued efforts to advance this approach toward clinical translation. Liver disease remains a major driver of morbidity and shortened lifespan in ZSD, and by targeting the underlying genetic defect, we aim to deliver meaningful, lasting improvements in patient health.”
The team focused on improving mouse models that mirror how ZSD develops in humans. Previous mouse models carrying these mutations often failed to survive, limiting their usefulness for studying disease progression. In contrast, the newly developed models from the Lutz lab survive and develop liver dysfunction that more closely mirrors the disease, including its long‑chain fatty acid biomarkers. The combination of treatments and a longitudinal biomarker increases the team’s confidence that the results could translate to patient care.
The researchers tested two different versions of the base editors in mice using viruses that delivered them directly to the liver. Both editors efficiently corrected the Zellweger mutation, but one called ABE8e-V106W was significantly better tolerated in the animals and made fewer unwanted edits.
By applying the editors to neonatal and older mice with the mutation, the team observed correction of the PEX1 gene in roughly 60% of liver cells. This was high enough to restore peroxisome and liver function and lower toxic buildup in the rest of the body. In cells derived from human patients, the editor corrected more than 80% of PEX1 mutations and restored peroxisome formation and function. The team also found evidence that correcting the PEX1 gene deficiency in the liver reduced toxic buildup in the brain, an early observation that suggests treating the liver could also ease neurological damage.
“What we observed in mouse livers with this permanent mutation fix was especially encouraging,” Presa said. “Next, we will explore different delivery modalities that in addition to the liver, will provide broader accessibility to the central nervous system. From a patient’s perspective, this has the potential for multiple organ system benefit that could impact quality of life issues, such as improved hearing and eyesight.”
In 2025, before the study was published, the early observations were compelling enough that the researchers recommended using the same gene-editing technology in Baby KJ’s treatment. The approach corrected a different mutation, helping save the newborn from a life-threatening rare metabolic disorder.
Lutz’s team plans to move the research towards more comprehensive treatment options. The idea is to develop and validate genetic therapies that can effectively treat severe genetic diseases like ZSD, move these into the latest FDA framework, and scale the application to treat more rare diseases more quickly.
“We’ve spent nearly a decade building deep expertise in rare diseases, not just by making patient mouse and cell models using them to demonstrate the safety and efficacy of emerging therapeutics, this is work that ultimately reshapes how clinical trials are designed and patients are treated today,” Lutz said. “We are looking forward to the next chapter with our collaborators at the Broad—moving these therapeutics into the clinic.”
Nature Biomedical Engineering
Experimental study
Animals
In vivo base editing rescues liver pathophysiology and peroxisome dysfunction in a mouse model of Zellweger spectrum disorder
14-Apr-2026