chief-andres-mateos-2022-nhp-ohc-primary

GROUNDING — Anc80L65 in non-human primate: ~90% IHC, essentially ZERO OHC

Why this was retrieved

Follow-up on chief-anc80l65-nhp-ohc-limitation.md. The Gadenstaetter 2024 review STATED that Anc80L65 reached only inner hair cells in NHPs; that was review-level evidence. This is the primary source it cited, retrieved to see the actual numbers, because h03’s deliv: 5 — the delivery score of the program’s top S-tier route — depends on them.

Exact queries

1. rag search "Anc80L65 synthetic AAV vector safe efficient gene transfer mammalian inner ear hair cell transduction" (found the review; primary absent from local corpus)
2. WebSearch: Andres-Mateos Landegger 2022 "Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate" Nat Commun 13:1359 PMC
3. WebFetch: https://pmc.ncbi.nlm.nih.gov/articles/PMC8924271/

Source

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.” Nature Communications 2022;13:1359. Open access, PMC8924271. Accessed 2026-08-21. NOT in the local BookLibrary corpus at retrieval time.

Verbatim passages

Dose and surgical route (identical across animals):

All animals … received an absolute dose of 2.5 x 10^11 vector genome copies (GC) in 30 ul

transmastoid facial recess exposure of the RWM with round window injection following oval window venting

INNER hair cells:

high transduction of the IHCs was detected for Anc80L65 in all cochlear regions

Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells

ranging from 90-30% for Anc80L65 … across the cochlea

(comparator: 30-5% with AAV1 across the cochlea; AAV1 was markedly less efficient at equal dose)

OUTER hair cells — the load-bearing passage:

only minimal outer hair cell (OHC) transduction was observed for both serotypes … Specifically, one positive outer hair cell was detected in the 32.0 kHz region of ear RA3009 and three appeared in the 22.6 kHz region of ear RA3128.

Species framing:

Unlike rodent models, the NHP cochlea has similar anatomy and proportions to humans.

Evidential weight — honest

• PRIMARY, open-access, quantitative. It STATES the claim; no bridging inference is needed for the core fact “Anc80L65 via round window transduced IHCs efficiently and OHCs essentially not at all in NHP.”
• Counted OHCs in the entire reported dataset: four (one in RA3009, three in RA3128). This is not a low percentage; it is a null result reported as individual cells.

What this does and does NOT establish

DOES establish:

• h03’s deliv: 5 cannot stand. Its stated basis is “Anc80L65; 60-100% cochlear transduction in OTOF trials precedent; single-vector” (hypotheses/h03-mini-strc/index.md). OTOF is an INNER-hair-cell gene, so the OTOF clinical precedent (Lv 2024, Wang 2023) evidences IHC transduction only. STRC is an OUTER-hair-cell protein. The one primate study of the same vector by the same route reports four transduced OHCs in total.
• The 60-100% OHC figure the vault attributes to Landegger 2017 is a MOUSE figure and does not survive the species jump for the cell type h03 requires.

Does NOT establish:

• That h03 is dead. Three real caveats, stated so the re-rank is not overcorrected:
  1. Dose. This NHP study used 2.5 x 10^11 GC in 30 ul. h03 quotes a clinical titer of 3.75 x 10^12 GC/mL. These are not directly comparable units (absolute GC vs concentration) and the study dose may be well below what h03 contemplates. No dose-response for OHC is available.
  2. Surgical route is a named variable in the paper’s own title (“Choice of vector AND SURGICAL APPROACH”). The vault’s other published STRC rescue precedent used a different route entirely: Shubina-Oleinik 2021 rescued Strc-KO mice with dual AAV9-PHP.B by UTRICLE injection (Gadenstaetter 2024 summary table). h03 is single-vector Anc80L65 by round window.
  3. A single study in two animals is thin, and negative OHC findings can be assay-sensitive.
• Therefore the honest move is a deliv DOWNGRADE with the gap named, not a kill, and not a re-derivation to some new specific number (which would be inventing a figure).

Follow-up filed

• Add sources/lit/2022-andres-mateos-anc80l65-nhp-cochlear-transfer.md (this paper).
• Add sources/lit/2017-landegger-anc80l65-inner-ear-nbt.md (Nat Biotechnol 35:280-284, PMC5340646) — the mouse figure the vault has been quoting for a year with no note behind it.
• Open question for h03, not answerable from this paper: is there ANY vector/route with demonstrated primate OHC transduction? If not, that is the real ceiling on h03 and it belongs in the hub.