Zellweger Syndrome

Overview

Zellweger syndrome is the severe end of the Zellweger spectrum disorder (ZSD), a group of inherited conditions caused by harmful variants in genes needed to build and maintain peroxisomes—small cell structures that process certain fats and help make important lipids. Severe disease usually presents in newborns with low muscle tone, feeding difficulty, seizures, brain and kidney abnormalities, and serious liver disease; intermediate and milder forms can instead cause progressive vision and hearing loss, neurologic problems, adrenal insufficiency, and liver dysfunction. GeneReviews: Zellweger Spectrum Disorder

The prognosis varies substantially by residual peroxisome function. Infants with severe ZSD typically die in the first year of life, whereas people with milder forms may survive into adulthood but can develop progressive multi-organ complications. Current care is supportive rather than curative: nutrition and feeding support, seizure treatment, hearing and vision care, liver and adrenal monitoring, fat-soluble vitamins, developmental services, and, in selected patients, cholic acid to reduce toxic bile-acid intermediates. GeneReviews: Zellweger Spectrum Disorder Cholic acid management in ZSD

Scope of Recent Research (2020–present)

Research activity has accelerated but remains small relative to more common genetic diseases. The field’s central questions are whether restoring PEX gene function can meaningfully reverse liver, retinal, and neurologic disease; how early treatment must begin; and how to deliver therapies safely across affected organs. The most consequential recent work targets the common partial-function PEX1 p.Gly843Asp variant with gene augmentation, RNA splice correction, and precision base editing, but no curative therapy has yet been tested successfully in people. AAV PEX1 retinal gene augmentation PEX1 base editing in mice and human cells Personalized PEX1 antisense program

Major Breakthroughs and Emerging Therapies

Precision gene editing is the clearest recent step toward addressing a root cause. In April 2026, investigators reported adenine base editing of the common human PEX1 p.Gly843Asp variant in patient-derived fibroblasts and in a matching Pex1 p.Gly844Asp mouse model. The approach uses a modified CRISPR-derived enzyme to change one disease-causing DNA letter without making a double-strand DNA break. In fibroblasts, editing corrected more than 80% of target PEX1 alleles and restored markers of peroxisome function. PEX1 base editing in mice and human cells

In mice, a one-time intravenous dual-AAV9 base-editor treatment achieved up to 60% correction of the mutant allele in bulk liver, improved growth, reduced abnormal very-long-chain and branched-chain fatty acids, normalized toxic C27 bile-acid intermediates, and substantially improved liver pathology. A non-viral lipid nanoparticle formulation delivering editor messenger RNA also corrected up to 27% of target alleles in bulk liver, offering a potentially more transient delivery route. These are major preclinical results, but they are not evidence of a human cure and primarily demonstrate rescue in liver rather than comprehensive correction of brain, eye, hearing, skeletal, and other disease manifestations. PEX1 base editing in mice and human cells

Gene augmentation has shown proof of concept for retinal disease. A 2021 study delivered a normal human PEX1 gene to the retina of PEX1 p.Gly844Asp mice using adeno-associated virus serotype 8 (AAV8) injected beneath the retina. Treated eyes showed partial biochemical correction and approximately two-fold better retinal electrical responses than control-treated eyes at later follow-up. This established that PEX1 gene replacement can improve retinal function in a model of milder PEX1-related ZSD, but it required local eye delivery and did not restore retinal responses to normal levels. AAV PEX1 retinal gene augmentation

RNA therapy may offer a personalized route for splice-altering mutations. A 2025 patient-specific research program developed splice-modulating antisense oligonucleotides (ASOs)—short synthetic nucleic acids designed to correct faulty RNA processing—for a child with a deep intronic PEX1 variant. In the child’s fibroblasts and induced pluripotent stem-cell lines, candidate ASOs increased correctly spliced PEX1 RNA two- to three-fold, increased PEX1 and PEX6 protein, improved peroxisomal protein import, lowered abnormal C26:0-lysophosphatidylcholine, and normalized depressed plasmalogen levels. The child died before a planned single-patient clinical trial could begin, so this remains laboratory evidence rather than a treatment outcome. Personalized PEX1 antisense program

Clinical Trials and Experimental Approaches

As of August 8, 2026, the publicly registered ZSD studies most relevant to therapeutic development are observational natural-history studies rather than interventional gene- or RNA-therapy trials. McGill University Health Centre’s recruiting Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders, NCT01668186, collects clinical, biochemical, imaging, and biospecimen data to define disease progression and develop endpoints for future trials. NCT01668186 natural-history study

A second recruiting observational study, ZSDvision (NCT06190626), sponsored by McGill University Health Centre/Research Institute, is prospectively tracking retinopathy through an estimated January 2029 completion date; no results had been posted. These studies do not test a treatment, but they are important for determining whether measures such as retinal imaging, visual function, lipid biomarkers, liver findings, and patient-reported outcomes can support future efficacy trials. NCT06190626 ZSDvision study ZSD ophthalmic natural-history study

Methodologies and Scientific Approaches

Researchers combine patient-derived skin fibroblasts, induced pluripotent stem-cell models, mouse models carrying the common PEX1 p.Gly844Asp-equivalent variant, and newer zebrafish models. These systems permit measurement of peroxisome assembly and protein import alongside clinically relevant biomarkers, including very-long-chain fatty acids, C26:0-lysophosphatidylcholine, branched-chain fatty acids, plasmalogens, and bile-acid intermediates. PEX1 base editing in mice and human cells Pex1 zebrafish model

Recent work also emphasizes better molecular diagnosis. RNA sequencing, reverse-transcription PCR, functional peroxisomal-import testing, and blood metabolite analysis can reveal deep intronic or splice-altering PEX1 variants that standard exome sequencing may miss—an essential step if an individual is to be matched to an allele-specific ASO or editing strategy. Multimodal diagnosis of peroxisome biogenesis disorders

Leading Institutions and Funding

Major contributors include McGill University and the Research Institute of the McGill University Health Centre, the Broad Institute of MIT and Harvard, Harvard University, the University of Southern California, The Jackson Laboratory, UMass Chan Medical School, Boston Children’s Hospital, Mass General Brigham, the University of Pennsylvania, Université de Montréal, and the Kennedy Krieger Institute. AAV PEX1 retinal gene augmentation PEX1 base editing in mice and human cells Personalized PEX1 antisense program

The 2026 base-editing study was supported through the NIH Somatic Cell Genome Editing Collaboration Opportunity Fund, NIH awards including U01 AI142756, RM1 HG009490, R35 GM118062, U54 OD020351, U54 OD030187, U42 OD010921, and R24 OD030033, as well as the Howard Hughes Medical Institute, the Global Foundation for Peroxisomal Disorders, and the Wynne Mateffy Research Foundation. Separately, the Oxford-Harrington Rare Disease Centre supports work at Boston Children’s Hospital toward individualized ASO therapy for PEX1-related ZSD. PEX1 base editing funding acknowledgements Oxford-Harrington PEX1 program

Strengths, Limitations, and Challenges

The strongest feature of the emerging pipeline is that it increasingly addresses disease biology upstream: gene augmentation supplies a working PEX1 copy, ASOs can repair certain abnormal PEX1 transcripts, and base editing can permanently correct a specific pathogenic DNA variant. The 2026 base-editing data are particularly encouraging because they showed molecular, metabolic, tissue-level, and growth benefits in animals, and because both viral and lipid-nanoparticle delivery were feasible. PEX1 base editing in mice and human cells

The limitations are substantial. ZSD is caused by variants in 13 different PEX genes, while the most advanced editing and augmentation programs are focused on PEX1 and often specifically on p.Gly843Asp; therefore, these approaches will not automatically help everyone with Zellweger syndrome. In the editing study, systemic treatment produced little expected editing in the central nervous system, and high-dose AAV treatment caused toxicity in mice under some conditions. Delivery to the brain and other organs, immune responses to AAV, long-term editor exposure, off-target effects, irreversible developmental injury before treatment, small patient populations, manufacturing cost, and equitable access all remain unresolved barriers. GeneReviews: Zellweger Spectrum Disorder PEX1 base editing in mice and human cells

Outlook and Future Directions

Zellweger syndrome is not close to a broadly available cure, but the field moved meaningfully closer between 2020 and August 2026: retinal PEX1 augmentation showed organ-targeted benefit in mice, individualized ASOs rescued a patient-specific splicing defect in cells, and base editing corrected the common PEX1 variant with major liver rescue in mice. The next milestones are replication in additional models, durable safety studies, delivery strategies that reach both liver and nervous system, and the first carefully monitored human studies. A realistic near-term goal is disease modification for genetically defined subgroups—especially PEX1 p.Gly843Asp-associated disease—rather than a single treatment that cures every form of ZSD. AAV PEX1 retinal gene augmentation Personalized PEX1 antisense program PEX1 base editing in mice and human cells

References

• GeneReviews: Zellweger Spectrum Disorder — Steinberg, Raymond, Braverman, and Moser; University of Washington, 2020.
• Cholic acid management in ZSD — Anderson et al., 2021.
• AAV PEX1 retinal gene augmentation — Argyriou et al., 2021.
• ZSD ophthalmic natural-history study — Yergeau et al., 2023.
• Personalized PEX1 antisense program — Thompson et al.; N1 Collaborative Annual Meeting, 2025.
• Multimodal diagnosis of peroxisome biogenesis disorders — Hsieh et al., 2025.
• Pex1 zebrafish model — Heins-Marroquin et al., 2025.
• NCT01668186 natural-history study — McGill University Health Centre/Research Institute of the McGill University Health Centre, 2026.
• NCT06190626 ZSDvision study — McGill University Health Centre/Research Institute of the McGill University Health Centre, 2026.
• PEX1 base editing in mice and human cells — Gao et al., 2026.
• PEX1 base editing funding acknowledgements — Gao et al.; Nature Biomedical Engineering, 2026.
• Oxford-Harrington PEX1 program — Oxford-Harrington Rare Disease Centre, 2025.