What they found
TL;DR (qwen3.6:35b): Researchers developed AAV-WM04, a novel AAV vector that efficiently and selectively targets inner hair cells in mice and non-human primates. This vector successfully restored hearing in a DFNB9 mouse model by delivering the large OTOF gene.
Efficient and cell-specific gene delivery to cochlear inner hair cells (IHCs) remains a major challenge for inner ear gene therapy. Here, we identify and characterize a novel AAV2-derived capsid, AAV-WM04, that enables highly efficient and selective IHC transduction at low doses. Using an in vivo-directed evolution strategy, we generated a randomized AAV2 capsid library with 9-amino acid insertions and performed iterative selection in the adult mouse cochlea. Next-generation sequencing revealed enrichment of several variants, among which AAV-WM04 exhibited superior packaging efficiency and pronounced IHC tropism. AAV-WM04 achieved near-complete IHC transduction throughout the cochlear axis in adult mice, outperforming clinically relevant vectors with minimal off-target expression and no detectable ototoxicity. Selective IHC transduction was observed in non-human primates following local delivery, providing proof-of-concept evidence supporting the translational potential of AAV-WM04. Therapeutically, AAV-WM04 enabled efficient dual-AAV trans-splicing delivery of the large OTOF gene, resulting in uniform full-length otoferlin expression in IHCs. In a humanized OtofQ829X/Q829X mouse model, AAV-WM04 restored auditory function across a broad frequency range at relatively low doses and achieved sustained hearing recovery. These findings establish AAV-WM04 as a next-generation IHC-targeted vector with high efficiency, safety, and cross-species applicability for precision gene therapy of hereditary hearing loss.
How this applies to our program
While this study focuses on OTOF/DFNB9 rather than STRC/DFNB16, it validates AAV-WM04 as a highly efficient and safe delivery vehicle for inner hair cells. This vector could be repurposed to deliver STRC gene therapies, potentially overcoming current challenges in achieving potent and sustained transduction of the target cell type.
Key numbers
- 9-amino acid insertions used in the randomized AAV2 capsid library
- Near-complete IHC transduction achieved throughout the cochlear axis in adult mice
- Sustained hearing recovery observed across a broad frequency range in the humanized mouse model
Links
- pubmed_id: https://pubmed.ncbi.nlm.nih.gov/42444129/
- DOI: https://doi.org/10.1016/j.ymthe.2026.07.021
Connections
[source]auto-indexed 2026-07-15 by strc-lit-watch