2026-05-12 理化学研究所
狙った膜タンパク質に結合できるAAVカプシドを合理的に設計する手法の開発
＜関連情報＞
- https://www.riken.jp/press/2026/20260512_1/index.html
- https://www.cell.com/iscience/fulltext/S2589-0042(26)00929-6
Ly6e/LY6E依存性AAVカプシド変異体の計算機支援による発見 Computationally guided discovery of Ly6e/LY6E-dependent AAV capsid variants
Hiroaki Ono ∙ Shoko Fujino ∙ Genshiro A. Sunagawa
iScience Published:April 1, 2026
DOI:https://doi.org/10.1016/j.isci.2026.115554
Highlights
- EvoPRAISE prioritized Ly6e-binding peptide inserts for AAV9 capsid display
- Cap-PF1.7 enabled widespread CNS gene delivery in Syrian hamsters after IV dosing
- Cap-PF1.7 showed Ly6e-dependent binding and transduction in cell-based assays
- EvoPRAISE identified multiple human LY6E-dependent AAV9 variants in vitro
Summary
Systemic adeno-associated virus (AAV) delivery to the central nervous system (CNS) would broaden neuroscience studies and therapeutic development, but capsids evolved in mice often underperform across species. We used structure-guided computational prioritization of short peptide inserts predicted to engage the BBB-associated Ly6-family receptor Ly6e/LY6E, grafting candidates into a surface loop of an AAV9 capsid. Selected variants increased blood-brain barrier transduction and enabled widespread CNS gene delivery in Syrian hamsters after intravenous dosing, with lead capsids showing Ly6e-dependent binding and transduction in cell assays. Using the same strategy for the human ortholog, we identified multiple AAV9 variants with LY6E-dependent enhancement of in vitro transduction. These capsids support species-matched CNS delivery and demonstrate how receptor-informed computation can focus experimental screening when in vivo library selection is impractical.
