chief-anc80l65-nhp-ohc-limitation

GROUNDING — Anc80L65 transduces OHCs in mouse but only IHCs in non-human primate

Why this was retrieved

Chief was checking the provenance of h03’s deliv: 5. The 2026-08-20 cure-route audit recorded that “the Anc80L65 adult-mouse transduction figures previously quoted in support of deliv: 5 have no sources/lit/ note”. Chief traced the figure to its in-vault citation:

hypotheses/h03-mini-strc/phases/STRC Anti-AAV Immune Response Model.md:142 “Landegger et al. (2017). A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nature Biotechnology 35(3):280-284. Anc80L65 60-100% OHC. PMC5340646”

Landegger 2017 is a REAL, retrievable paper (not a phantom), but it has no note in sources/lit/. While searching for it, a stronger and disconfirming result surfaced.

Exact query

rag search "Anc80L65 synthetic AAV vector safe efficient gene transfer mammalian inner ear hair cell transduction"

Landegger 2017 itself is NOT in the local corpus — it appears only inside the reference list of Jiang 2024 (hit #1). Hit #2 was the passage below.

Index path

~/Knowledge/BookLibrary/mineru-output/Gadenstaetter_2024_Inner-ear-gene-therapy-bench-bedside_MolDiagTher/Gadenstaetter_2024_Inner-ear-gene-therapy-bench-bedside_MolDiagTher/auto/Gadenstaetter_2024_Inner-ear-gene-therapy-bench-bedside_MolDiagTher.md

Line 127 (section “5 Outlook”, PDF pp.14-15).

Verbatim passage

While several vectors are capable of doing that, two vectors often used to transduce additional targets are AAV9-PHP.B and Anc80L65, both being synthetic AAV variants [31]. AAV9-PHP.B has formerly been investigated for its ability to cross the blood-brain barrier in C57BL/6 mice and was only later found to also efficiently transduce inner ear cells in other mouse strains and NHPs [162]. On the contrary, Anc80L65 was initially found to transduce both inner and outer hair cells in mice but application of this vector in NHPs only displayed effective transduction of inner hair cells [40]. These examples highlight the need for suitable vectors as well as of studies in appropriate large animal models.

Source: Gadenstaetter AJ et al., “Inner Ear Gene Therapy: An Overview from Bench to Bedside”, Molecular Diagnosis & Therapy, 2024.

Its reference [40], verbatim from line 200 of the same file:

40. Andres-Mateos E, Landegger LD, Unzu C, Phillips J, Lin BM, Dewyer NA, et al. Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate. Nat Commun. 2022;13:1359.

Note that L.D. Landegger is an author on BOTH the 2017 mouse paper the vault cites and the 2022 NHP paper that qualifies it.

Second passage from the same file (line 95, the model-summary table)

The only published STRC rescue in the table is:

STRC | OHCs | Strc-KO | P0-P1 | Dual AAV9-PHP.B | Utricle injection | Hearing improvement (thresholds: 50 dB) up to 3 months after treatment | Shubina-Oleinik et al. (2021)

i.e. dual AAV9-PHP.B via utricle injection, not single-vector Anc80L65 via round window.

Evidential weight — honest

• This is a REVIEW (secondary source) that STATES the claim. It is not the primary measurement.
• The primary source, Andres-Mateos 2022 Nat Commun 13:1359, is NOT in the local corpus and has no sources/lit/ note. Under STRC AGENTS.md section 0c the claim is therefore LIT-ANCHORED-VIA-REVIEW, one step weaker than a parsed primary. It must be retrieved before any deliv figure is re-derived from it.
• What it is strong enough to do RIGHT NOW: withdraw the unqualified deliv: 5. A score cannot rest on a mouse OHC figure once a review of the field states in plain terms that the same vector failed to reach OHCs in primates.

Bridging derivation (why this bears on h03 specifically)

1. STRC/stereocilin is expressed in OUTER hair cells. The same review’s own table records STRC | OHCs. h03 needs OHC transduction, not IHC transduction.
2. h03’s deliv: 5 is justified by “Anc80L65; 60-100% cochlear transduction in OTOF trials precedent; single-vector” (hypotheses/h03-mini-strc/index.md).
3. The OTOF precedent is an IHC precedent — otoferlin is an inner-hair-cell protein (the review: “appropriate vectors must transduce cochlear inner hair cells where otoferlin exerts its crucial role”). So the clinical OTOF success transfers to h03 only if the vector reaches OHCs as well as IHCs in a primate.
4. Per the passage above, that is exactly what Anc80L65 failed to do in NHPs.
5. Therefore h03’s deliv: 5 rests on a species-and-cell-type extrapolation that the field’s own review contradicts. This does NOT kill h03 — the mouse OHC result is real and the surgical approach is a named variable in the 2022 title (“Choice of vector AND SURGICAL APPROACH”) — but deliv: 5 (best possible) is not defensible.

Status

Recorded because it cuts against the program’s interest. Feeds the C4 re-rank. Follow-up filed: retrieve Andres-Mateos 2022 (Nat Commun 13:1359) and Landegger 2017 (Nat Biotechnol 35:280-284, PMC5340646) into sources/lit/.