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Article

Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice

by
Christian P. Joschko
1,
Chih-Chieh Wang
2,
Azuwerus van Buiten
1,
Maaike Goris
1,
Femke Hoogstra-Berends
1,
Joy Wang
2,
Jan Henric Bacurio
2,
Yinxing Chen
2,
Nannan Jia
2,
June Deng
2,
Shiliang Hu
2,
Mariana Nacht
2,
Matthew J. Chiocco
2,
Robert H. Henning
1 and
Leo E. Deelman
1,*
1
Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
2
Alexion Pharmaceuticals, AstraZeneca Rare Disease, Genomic Medicine, 100 Binney Street, Cambridge, MA 02142, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(7), 3338; https://doi.org/10.3390/ijms27073338
Submission received: 11 March 2026 / Revised: 1 April 2026 / Accepted: 4 April 2026 / Published: 7 April 2026
(This article belongs to the Section Molecular Biology)
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Abstract

Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 1012 or 3 × 1013 vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy.
Keywords: homocystinuria; cystathionine β-synthase; transsulfuration; gene therapy; adeno-associated virus; methylation; hyperhomocysteinemia; multi-omics homocystinuria; cystathionine β-synthase; transsulfuration; gene therapy; adeno-associated virus; methylation; hyperhomocysteinemia; multi-omics

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MDPI and ACS Style

Joschko, C.P.; Wang, C.-C.; van Buiten, A.; Goris, M.; Hoogstra-Berends, F.; Wang, J.; Bacurio, J.H.; Chen, Y.; Jia, N.; Deng, J.; et al. Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice. Int. J. Mol. Sci. 2026, 27, 3338. https://doi.org/10.3390/ijms27073338

AMA Style

Joschko CP, Wang C-C, van Buiten A, Goris M, Hoogstra-Berends F, Wang J, Bacurio JH, Chen Y, Jia N, Deng J, et al. Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice. International Journal of Molecular Sciences. 2026; 27(7):3338. https://doi.org/10.3390/ijms27073338

Chicago/Turabian Style

Joschko, Christian P., Chih-Chieh Wang, Azuwerus van Buiten, Maaike Goris, Femke Hoogstra-Berends, Joy Wang, Jan Henric Bacurio, Yinxing Chen, Nannan Jia, June Deng, and et al. 2026. "Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice" International Journal of Molecular Sciences 27, no. 7: 3338. https://doi.org/10.3390/ijms27073338

APA Style

Joschko, C. P., Wang, C.-C., van Buiten, A., Goris, M., Hoogstra-Berends, F., Wang, J., Bacurio, J. H., Chen, Y., Jia, N., Deng, J., Hu, S., Nacht, M., Chiocco, M. J., Henning, R. H., & Deelman, L. E. (2026). Liver-Targeted AAV-DJ-hCBS Therapy Achieves Long-Term Correction of Metabolic Imbalance in CBS-Deficient Mice. International Journal of Molecular Sciences, 27(7), 3338. https://doi.org/10.3390/ijms27073338

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