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Scientific Frontline: Extended "At a Glance" Summary: Base Editing for Zellweger Spectrum Disorder
The Core Concept: Base editing, a highly precise gene-editing technology, has successfully corrected the PEX1 genetic mutation responsible for Zellweger spectrum disorder in a mouse model, significantly restoring liver and peroxisome function.
Key Distinction/Mechanism: Unlike traditional gene-editing methods that rely on double-stranded DNA breaks, base editing utilizes a deaminase enzyme to make single-letter DNA changes without cutting the helix. Specifically, the adenine base editor ABE8e-V106W was utilized for its optimized properties, offering high on-target mutation correction while maintaining remarkably low off-target activity.
Major Frameworks/Components:
- Adenine Base Editors (ABEs): Specialized enzymes, such as ABE8e-V106W, that chemically convert specific pathogenic DNA base pairs into healthy sequences.
- PEX1 Gene: The target genetic sequence where the primary mutation causes a severe loss of cellular function.
- Peroxisomes: Tiny cellular organelles responsible for breaking down metabolic byproducts, which fail to function in Zellweger spectrum disorder but were rescued by the base edit.
- Adeno-Associated Virus (AAV) Vectors: The viral delivery vehicles utilized in the study to transport base editors directly into the targeted liver cells.
Branch of Science: Molecular Genetics, Biomedical Engineering, and Gene Therapy.
Future Application: The successful validation in an in vivo mammalian model establishes a pathway toward human clinical trials targeting the root cause of Zellweger spectrum disorder. Researchers are actively working to optimize lipid nanoparticles as a delivery system and intend to apply this precision gene-editing framework to treat other rare peroxisomal diseases caused by PEX gene mutations.
Why It Matters: Zellweger spectrum disorder is a severe, life-threatening metabolic condition affecting 1 in 50,000 to 90,000 births in North America, currently lacking any curative therapies. Demonstrating that base editing can safely reverse the condition's pathology and clear toxic metabolites establishes a critical precedent for translating precision genetic surgery into viable clinical interventions for thousands of currently untreatable rare diseases.
In 2025, baby KJ Muldoon became the first person to receive a personalized gene editing treatment, which likely saved his life. But the scientific advances that made the groundbreaking treatment possible were years in the making long before KJ was born. One was base editing, the technology developed in 2016 by David Liu and his lab at the Broad Institute that makes single-letter changes in DNA and was used to correct KJ’s life-threatening mutation.
Another advancement was the development and characterization of a specific version of a key base editor component: the enzyme called a deaminase, which converts a disease-causing DNA letter into a healthy one. Efforts to identify an optimal deaminase for a different genetic disorder began in 2020 in a collaboration between Liu’s lab and scientists from Jackson Laboratory and the University of Southern California (USC). The results of this project, published today in Nature Biomedical Engineering, were so compelling that they spurred Liu to recommend using the same deaminase in KJ’s treatment when the child’s doctors approached him in early 2025, even before the findings were published.
In the new study, Liu and his team, in collaboration with scientists led by Cat Lutz at the Jackson Laboratory and Joe Hacia at USC, showed that base editing can correct mutations in the PEX1 gene that cause Zellweger spectrum disorder , a rare, life-threatening condition that leads to liver and brain damage and is unrelated to KJ’s disease. The team demonstrated that this base edit, when made in a mouse model of the disorder, restored function of the liver and of peroxisomes — tiny fluid-filled sacs in cells that break down metabolic byproducts but are impaired as a result of the PEX1 mutation.
The authors tested two different base editors in mice — one called ABE8e and a modified version called ABE8e-V106W — and found that both efficiently corrected the PEX1 mutation, but ABE8e-V106W was significantly better tolerated in the animals and made fewer off-target edits. When Kiran Musunuru of the University of Pennsylvania Perelman School of Medicine, one of baby KJ’s lead doctors, asked Liu which deaminase he and his team should use to correct KJ’s disease-causing mutation, Liu recommended ABE8e-V106W based on the data reported in today’s publication.
“These observations, well before the data was published, suggested that ABE8e-V106W is an adenine base editor that sits in the Goldilocks zone, where it offers both high on-target activity that can efficiently correct a pathogenic mutation, and relatively low off-target activity that reduces the frequency of unwanted edits,” said Liu, Richard Merkin Professor, and director of the Merkin Institute for Transformative Technologies in Healthcare at Broad the Dudley Cabot Professor of the Natural Sciences in the Faculty of Arts and Sciences at Harvard University, and Howard Hughes Medical Institute investigator.
“It’s easy to assume that rescuing this quite-rare peroxisome disorder in mice wouldn’t have anything to do with saving a human baby with a very different life-threatening disease. But, it actually had a lot to do with it. It goes to show how science builds on itself, and how sharing the latest unpublished findings at a key moment can inform important decisions in the cutting-edge treatment of patients,” Liu added.
The findings pave a path toward treating the root genetic cause of Zellweger spectrum disorder, a metabolic disease that affects about 1 in 50,000 to 90,000 births in North America.
“Correcting the most common PEX1 mutation is just the beginning of building meaningful treatment strategies for patients with Zellweger spectrum disorder, who currently have no options that treat the cause of the disease,” said lead author Xin “Daniel” Gao, now an Assistant Professor at the University of Pittsburgh, who led the project as a postdoctoral fellow in Liu’s lab. “More broadly, this work lays the foundation for using precision gene editing to develop better treatments for other rare peroxisomal diseases caused by mutations in PEX genes.”
“A great deal of work went into the mouse modeling for this project. Ultimately, we developed a model that faithfully reproduces the disease and its long-chain fatty acid biomarkers, giving us strong confidence that these findings will translate into the clinic. This collaboration between David’s and my labs represents one of many joint efforts and serves as a cornerstone for future therapeutic advances emerging from the Center for Genetic Surgery,” said Lutz, co-senior author of the study and vice president of the Rare Disease Translational Center at Jackson Laboratory.
Translational potential
In their study, the researchers administered base editors to neonatal and older mice with the PEX1 variant, using two adeno-associated viruses, which delivered the base editors to the livers of the animals. The team revealed that the base editor corrected the PEX1 gene in roughly 60 percent of liver cells, high enough to restore peroxisome and liver function and lower the buildup of toxic metabolites throughout the body.
The scientists also showed that the editing efficiency 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 the team tested.
According to Liu, more research is needed to translate this work in mice into a potential treatment for humans. For example, the authors showed that the base editing system could be reformulated to be delivered using lipid nanoparticles, which have been used in several treatments for humans including KJ’s. However, further optimization of nanoparticle delivery of the base editor to treat Zellweger spectrum disorder (ZSD) remains to be done.
One of Liu’s ultimate goals is to make personalized gene editing treatments accessible to patients on a broader scale through the new Center for Genetic Surgery (CGS) that he co-leads at Broad.
“Currently, candidate CGS programs are ones for which a base or prime editor has been shown to correct a pathogenic mutation back to a healthy sequence, resulting in at least partial rescue of the disease in an animal model,” Liu said. “Demonstrating benefit to animals provides the foundation to move the study towards a clinical trial that we hope will eventually benefit patients with few treatment options.”
“There is an urgent unmet need to develop and implement targeted therapies that address the root causes of thousands of genetic disorders. I am honored that our work on a common form of ZSD may have broader impact across other genetic diseases,” said Hacia, co-senior author and medical geneticist at the Keck School of Medicine of University of Southern California. “Many children with ZSD develop life-threatening liver disease, leading to frequent hospitalizations and a shortened lifespan. We are driven by the hope of changing that reality and look forward to advancing this work into clinical trials to address liver disease in ZSD and related pathologies in other affected organs.”
Funding: This work was supported by the National Institutes of Health, the Global Foundation for Peroxisomal Disorders, and Wynne Mateffy Research Foundation.
Published in journal: Nature Biomedical Engineering
Authors: Xin D. Gao, Maximiliano Presa, Jordyn E. Duby, Jennifer Ryan, Pierre-Alexandre Piec, Alvin Hsu, Samagya Banskota, Allen Yujie Jiang, Lingxiao Chen, Gregory A. Newby, Erminia Di Pietro, Jonathan M. Levy, Bradford H. Steele, Sarah Lecordier, Fangfei Qin, Ann B. Moser, Jun Xie, Guangping Gao, Nancy E. Braverman, Aamir R. Zuberi, Joseph G. Hacia, Cathleen M. Lutz, and David R. Liu
Source/Credit: Broad Institute | Jessica Colarossi
Reference Number: gen041426_01
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