Abstract
Alpha-1 antitrypsin (A1AT) deficiency (AATD) is caused by a mutation in the SERPINA1 gene (PiZ allele), where misfolded A1AT liver accumulation leads to liver damage, and A1AT deficiency in the lungs results in emphysema due to unregulated neutrophil elastase activity. Base editing offers a potential cure for A1AT; however, effective treatment is hindered by the absence of dual-target delivery systems that can target key tissues. We developed Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) to deliver base editors to the liver and lungs. Dual SORT LNPs correct the PiZ mutation, achieving 40% correction editing in liver cells and 10% in lung AT2 cells. The liver maintains stable editing for 32 weeks, reducing Z-A1AT levels by over 80% and restoring a normal liver phenotype. In parallel, 89% neutrophil elastase inhibition is achieved in lung bronchoalveolar lavage fluid. Taken together, Dual SORT LNP therapy offers a promising approach for long-lasting genome correction for multi-organ diseases such as AATD.
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Data availability
All data needed to evaluate the conclusions in this paper are present in the main text and the supplementary material. The flow cytometry raw data are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by a Sponsored Research Agreement with ReCode Therapeutics and the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 EB025192-01A1). The UT Southwestern Small Animal Imaging Shared Resource is supported, in part, by the National Cancer Institute (P30CA142543) and the Cancer Prevention & Research Institute of Texas (RP210099). The authors would like to thank UT Southwestern Metabolic Phenotyping Core for the analysis of blood biochemicals; UT Southwestern Small Animal Imaging Resource for their shared AMI-HTX; UT Southwestern Tissue Management Shared Resource for helping with histology and H&E staining; UT Southwestern Proteomics Core for the analysis of A1AT isoforms; UT Southwestern Whole Brain Microscopy Facility for helping with slide scanning; the Moody Foundation Flow Cytometry Facility for helping with flow cytometry and providing expertise; and Inotiv histology and digital pathology services. The authors would also like to thank P. Hartono, L. Kahn, S. Sherman, M. Weinberg and J. Couch for their support.
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Conceptualization: M.K. and D.J.S. Methodology: M.K. Investigation: M.K., E.S.S., J.C.C., S.C., Y.S., S.M.L., S.W., P.P., Z.T., A.K., B.A.W. and D.J.L. Visualization: M.K. and D.J.S. Resources: D.J.S. Project administration: D.J.S. Supervision: S.C. and D.J.S. Writing—original draft: M.K. and D.J.S. Writing—review and editing: D.J.S. Funding acquisition: D.J.S.
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A provisional patent application covering compositions, methods and uses for targeting cystic fibrosis and related disorders has been filed by UT Southwestern. D.J.S. is a co-founder and member of the scientific advisory board of ReCode Therapeutics, which has licensed intellectual property from UT Southwestern. D.J.S. discloses financial interests in ReCode Therapeutics, Signify Bio, Jumble Therapeutics and Tome Biosciences. J.C.C., A.K., B.A.W. and D.J.L. are employees of ReCode Therapeutics and have stock options in the company. All other authors declare that they have no competing interests.
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Additional Supplementary Methods, DNA template sequences of Cas9 and ABEs, Methods-only references, Supplementary Figs. 1–17 and Supplementary Tables 1–5
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Kim, M., Song, E.S., Chen, J.C. et al. Dual SORT LNPs for multi-organ base editing. Nat Biotechnol (2025). https://doi.org/10.1038/s41587-025-02675-z
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DOI: https://doi.org/10.1038/s41587-025-02675-z
