STRC Research

OHC-Specific Gene Delivery

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OHC-Specific Gene Delivery

Getting a gene into an OHC is not the hard part. AAV-ie does it efficiently — near 100% transduction in all cochlear cells at P2 with a CAG promoter. The hard part is getting it only into OHCs.

Why does this matter? Three reasons:

  1. Safety: Off-target expression of a structural protein like prestin or STRC in the wrong cell type can cause toxicity or immune response.
  2. Dose efficiency: If your vector leaks into IHCs, brain, liver, and vestibular cells, you’re wasting vector. The effective OHC dose drops, the off-target risk rises.
  3. Regulatory pathway: FDA expects you to know where your vector goes. Cell-type specificity data is a prerequisite for IND filing.

The CAG problem: CAG (CMV enhancer + chicken beta-actin promoter) is ubiquitous. In cochlea it drives expression everywhere: OHCs, IHCs, SCs, vestibular HCs, spiral ganglion neurons. And it causes mislocalization of structural proteins. Zhao et al. 2025 showed CAG-prestin didn’t even rescue hearing in Slc26a5 KO mice despite some prestin expression — probably because IHC ectopic expression disrupted something.

The Myo15 situation: The current state of the art for OHC targeting in STRC therapy uses the Myo15 promoter. It’s better than CAG but still hits some IHCs and has limited efficiency. It works, as shown by the Holt lab 2021 paper, but leaves room for improvement.

The B8 approach: Zhao et al. 2025’s synthetic B8 enhancer achieves ~100% OHC transduction in all three cochlear turns with zero off-target in IHCs, vestibular HCs, brain, heart, or liver. And it works in adults. This is the bar STRC therapy should aim for: not just “good enough to rescue in mice” but specific enough for a clean safety profile in humans.

The ARBITER pipeline is the tool: If you apply ARBITER to the STRC locus, you can find the native regulatory elements, then engineer a synthetic enhancer optimized for both efficiency and specificity. This is the path from current mouse-level results to human-grade OHC targeting.

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