2026-01-28 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202512/t20251229_1143167.shtml
- https://www.cell.com/cell/abstract/S0092-8674(25)01488-6
AAVLINK: 遺伝子治療における大量輸送のための強力なDNA組換え法 AAVLINK: A potent DNA-recombination method for large cargo delivery in gene therapy
Jianbang Lin ∙ Yunping Lin ∙ Nana Liu ∙ … ∙ Taian Liu ∙ Yuwu Jiang ∙ Zhonghua Lu
Cell Published:January 27, 2026
DOI:https://doi.org/10.1016/j.cell.2025.12.039
Graphical abstract
Highlights
- AAVLINK enables delivery of large genes beyond standard AAV capacity
- AAVLINK achieves higher efficiency with fewer by-products than current methods
- Restores behavior and reduces seizures in mouse models with therapeutic genes
- Validates a resource of 198 large genes suitable for gene reconstitution applications
Summary
Delivery of therapeutic genes is essential for successful gene therapy. Adeno-associated viruses (AAVs) are a prime vector for carrying gene cargoes. However, the limited packaging capacity of AAVs poses a major challenge for large gene transduction. Here, we devised a strategy termed AAV with translocation linkage (AAVLINK), leveraging Cre/lox-mediated intermolecular DNA recombination to overcome cargo size constraints. This AAVLINK strategy enabled superior gene segmentation flexibility, robust gene reconstitution efficiency, and a marked reduction in truncated protein products. AAVLINK drove expression of intact Shank3 or SCN1A and rescued behavior and seizure phenotypes of mutant mice, respectively. Moreover, we generated AAVLINK2.0 with destabilized Cre to address biosafety concerns. Importantly, we used AAVLINK to build a vector bank for 193 large genetic-disorder-associated genes and 5 CRISPR-based tools with verified gene reconstitution. Altogether, our study establishes a robust method to facilitate delivery of large gene cargoes using AAVs.
