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Nat. Biotechnol., Jun 02 2025, | https://doi.org/10.1038/s41587-025-02675-z
Dual SORT LNPs for multi-organ base editing
Minjeong Kim 1, Eunice S. Song 1, Joseph C. Chen 2, Sumanta Chatterjee 1, Yehui Sun 1, Sang M. Lee 1, Shiying Wu 1, Priyanka Patel 1, Zeru Tian 1, Ariel Kantor 2, Brandon A. Wustman 2, David J. Lockhart 2 & Daniel J. Siegwart 1 *
1Department of Biomedical Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center, Program in Genetic Drug Engineering, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
2ReCode Therapeutics, Menlo Park, CA, USA.
2ReCode Therapeutics, Menlo Park, CA, USA.
*Corresponding author: correspondence to Daniel J. Siegwart
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.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-09)
- 국외 연구진
- 바이오·의료융합 > 바이오소재
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