Zhao 2025 — Deciphering Enhancers for Hearing Loss Genes
Full title: Deciphering enhancers of hearing loss genes for gene therapy
Journal: Neuron (2025)
Authors: Zhao et al.
RAG book name: Zhao_2025_Deciphering-enhancers-hearing-loss-genes-gene-therapy
Why It Matters for Misha
Addresses a fundamental problem in gene therapy: how do you make a gene express in the right cells (OHCs specifically) and at the right level? Relevant for any STRC gene therapy vector design.
Key Findings
- Introduces ARBITER workflow (AAV-reporter-based in vivo transcriptional enhancer reconstruction)
- Applied to Slc26a5 (encodes prestin, OHC motor protein) and Myo7a (hair cell, Usher syndrome)
- Found conserved non-coding elements (CNEs) in gene introns act as transcriptional enhancers
- Slc26a5-E1 + E2 together control precise OHC-specific prestin expression
- Knockout E1 alone: progressively reduced prestin, hearing loss
- Knockout both: prestin completely absent, severe hearing loss
- Enhancer B8 successfully restores hearing sensitivity in Slc26a5 knockout mice
- Broadly applicable: workflow can identify cell-type-specific enhancers for any hearing loss gene
Why STRC-Relevant
- STRC gene therapy needs OHC-specific promoters to drive stereocilin expression correctly
- ARBITER-style enhancer discovery could identify optimal regulatory elements for STRC vectors
- More specific promoters = fewer off-target effects = safer gene therapy
Connections
- Iranfar 2026 - Dual AAV STRC DFNB16 — STRC vector design benefits from this regulatory knowledge [see-also]
- Omichi 2020 - AAV Hair Cell Transduction — OHC specificity is a shared challenge [see-also]
- STRC Gene Therapy Research [applies]