2024 Lv — AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial
AAV1-hOTOF dual-vector gene therapy: 6 DFNB9 children, round window injection, 5/6 hearing recovery at 26 weeks (ABR 106→52 dB avg); dual-AAV via RNA trans-splicing; Fudan University trial.
Citation
Lv J, et al. “AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.” Lancet. 2024 May 25;403(10441):2317-2325 (epub Jan 24, 2024). DOI: 10.1016/S0140-6736(23)02874-X. PMID: 38280389. Eye & ENT Hospital, Fudan University, Shanghai (Huawei Li lab / Yilai Shu group).
ERRATUM: Lancet 2024;403(10441):2292, PMID 38796209 — minor correction published.
NOTE: This is the primary source for the “Sun 2024 Lancet” reference in dual_vector_otof_calibration.py. The first author is Lv, not Sun. “Sun et al. 2024” cited in the script likely conflates this Fudan University trial (Lv et al.) with a different paper. The script’s cited “Sun et al. 2024 (Lancet)” titer data (cohort 3, ~5×10¹¹ GC/ear) should be attributed to this Lv 2024 Lancet paper.
TL;DR
First-in-human AAV1 dual-vector gene therapy for DFNB9 (otoferlin deafness). Dual-rAAV system uses RNA trans-splicing (splicing donor/acceptor) to reconstitute full-length OTOF cDNA beyond single-AAV capacity. Six pediatric patients (ages 1-6) received unilateral round window injection. Five of six showed hearing recovery: ABR threshold improved from ~106 dB pre-treatment to ~38-55 dB at 26 weeks in responsive patients. No dose-related toxicity. One patient with pre-existing AAV neutralizing antibodies failed to respond.
Numbers that matter
| Parameter | Value | Units | Source | Uncertainty |
|---|---|---|---|---|
| Patients enrolled | 6 | children (1-6 yrs) | text | unilateral treatment |
| Responders at 26 weeks | 5/6 | — | Abstract | 1 non-responder (AAV NAbs) |
| Mean pre-treatment ABR threshold | ~106 | dB HL | text | profound deafness |
| Mean post-treatment ABR threshold (26 wk) | ~38-55 | dB HL | text | 5 responders |
| Mean ABR improvement | ~52 dB (reported avg) | dB HL | reported in summaries | across responders |
| AAV serotype | AAV1 | — | title | |
| Delivery mechanism | dual-rAAV RNA trans-splicing (SD/SA) | — | text | |
| Route | round window membrane injection | — | text | |
| Follow-up | 26 weeks (primary endpoint) | — | text | |
| Safety | no dose-related toxicity; no SAEs | — | text | |
| Titer used | not reported in public summaries available | GC/ear | text | full titer data in paper — exact values not retrieved |
Note on titer: The dual_vector_otof_calibration.py script assigns “cohort 3 (Sun 2024)” ~5e11 GC/ear. This likely refers to this Lv 2024 Lancet Fudan trial, but the exact titer used per ear is in the full paper methods section and not confirmed from available text. The DB-OTO trial (Lustig NEJM 2025) used 7.2×10¹² vector genomes per ear — substantially higher.
Method essentials
- Institution: Eye & ENT Hospital, Fudan University, Shanghai
- Capsid: AAV1
- Dual-vector strategy: RNA trans-splicing via SD/SA sequences to reconstitute full-length hOTOF
- Injection: round window membrane (cochleostomy approach)
- Age at treatment: 1-6 years old
- Primary endpoint: ABR threshold ≤70 dB HL at 26 weeks
Limitations
- Small n=6, unilateral only
- Exact titer per ear and dose-cohort breakdown requires full paper access
- Trans-splicing efficiency is lower than non-spliced delivery; introduces recombination step
- No adult data
- Non-responder was a child with pre-existing AAV1 NAbs (humoral immunity consideration)
Relevance to STRC
Provides the clinical precedent that dual-rAAV cochlear gene therapy is safe and efficacious in pediatric patients. Calibrates the dual_vector_otof_calibration.py model for clinical titer ranges. The dual-vector efficiency data (co-transduction + recombination) from this trial informs the h03 decision to pursue single-vector (Ultra-Mini STRC fits without dual-vector).
Connections
[part-of]aav-cochlear-delivery[supports]STRC Dual-Vector vs Single-Vector Transduction[applies]h03 hub[see-also]2026-01-iranfar-dual-aav-strc-ctm