Fudan University Leads Gene Therapy Breakthrough Restoring Hearing in Hereditary Deafness Children

Fudan's Pioneering Dual-AAV Approach to Overcoming Gene Size Barriers

The core innovation from the Fudan team lies in their dual adeno-associated virus (AAV) vector strategy. The OTOF gene, which encodes the otoferlin protein crucial for neurotransmitter release in inner ear hair cells, is too large—over 6 kilobases—to fit into a single AAV capsid, the standard vehicle for gene delivery due to its safety profile and low immunogenicity. Traditional AAVs have a packaging limit of about 4.7 kb, prompting researchers worldwide to truncate genes or use alternative vectors with higher risks. Fudan's solution splits the OTOF coding sequence across two AAV1 vectors (AAV1-hOTOF), which recombine inside target cells to form the full functional gene.

This method was rigorously tested in preclinical models. In OTOF-knockout mice and non-human primates, dual-AAV delivery restored otoferlin expression in cochlear hair cells and synapses, yielding auditory brainstem response (ABR) improvements of 30–50 dB. The vectors showed stable expression up to 12 months post-injection, with no off-target effects or tumorigenesis. Injection via the round window membrane—a minimally invasive surgical route—ensured precise delivery to the cochlea while minimizing trauma, a technique refined through custom micro-catheter development.

Clinically, the drug RRG-003 (developed with Shanghai Dingxin Gene Technology) was dosed at 9×10¹¹ or 1.5×10¹² vector genomes per ear. Patients received perioperative steroids to curb inflammation, a common AAV challenge. Follow-up included serial ABR, otoacoustic emissions (OAE), speech audiometry, and immunological monitoring, confirming transgene persistence without humoral or cellular immune rejection spikes.

Unilateral Trial: First Proof-of-Concept in Humans

Launched in October 2022 after ethics approval in June, the phase 1/2 single-arm trial (ChiCTR2200063181) enrolled six children aged 1–13 with confirmed biallelic OTOF mutations and profound hearing loss (>95 dB ABR bilaterally). One received low dose; five high dose, injected unilaterally.

• Auditory Recovery: Five showed ABR thresholds dropping to 45–68 dB (0.5–4 kHz) by week 26, enabling conversational hearing without aids.
• Speech Perception: Mandarin infant-toddler meaningful auditory integration scale (IT-MAIS) scores rose from near-zero to 30+ points; categories of auditory performance (CAP) reached level 4 (understands simple phrases).
• No Response in One: The low-dose patient had partial improvement (to 68 dB), suggesting dose optimization.

Published in The Lancet (Jan 2024), results marked the first human evidence of gene therapy reversing DFNB9 deafness, with children responding to voices, music, and environmental sounds within weeks.Read the full Lancet paper

Bilateral Success: Hearing in Both Ears and Sound Localization

Building on unilateral success, Fudan's interim analysis of a bilateral extension trial (published Nature Medicine, Jun 2024) treated five children (median age 2.8 years) in both ears simultaneously. ABR thresholds improved symmetrically: e.g., one patient reached 58 dB bilaterally by week 26. Distortion product otoacoustic emissions (DPOAE) partially recovered, indicating hair cell function restoration.

Key milestones:

• Week 4: ABR emergence, sound detection.
• Week 13: Speech recognition ('mama', 'baba'), CAP level 3–4.
• Week 26: Sound localization (root mean square error from 93° to 40°), music appreciation, no aids needed.

This binaural approach addresses real-world needs, as unilateral therapy leaves one ear deaf.

Safety Profile and Long-Term Monitoring

AAV1's neurotropism suits inner ear delivery, but risks like inflammation or insertional mutagenesis were mitigated. Trials reported no serious adverse events; grade 3 events limited to transient neutropenia. Neutralizing antibodies rose post-treatment but didn't impair efficacy. Ongoing monitoring (up to 2+ years) tracks durability, with stable ABR in the longest case.

Fudan's NHC Key Lab of Hearing Medicine ensures GMP-compliant production, vital for scaling.

Photo by KG Baek on Unsplash

Fudan University's Research Ecosystem Driving Innovation

Fudan University, a C9 League powerhouse, hosts the Eye & ENT Hospital as a national clinical research center. Prof. Shu Yilai (PhD Harvard, back since 2018) leads the Inherited Hearing Loss Center, blending basic science (CRISPR screens, single-cell RNA-seq) with translation. Collaborations with Harvard's Mass Eye & Ear (Prof. Zheng-Yi Chen) and Southeast U. exemplify Sino-US synergy.

China's national push—'Healthy China 2030'—funds such work, with Fudan securing grants for rare disease gene therapies. This positions Chinese universities as global biotech leaders, attracting talent amid higher ed jobs boom in biomed.

Global Context: Fudan Sets the Pace

Fudan's trials precede Regeneron's DB-OTO (phase 1/2, US 2025 data: hearing recovery in 11 kids) and others targeting OTOF/TMC1. Worldwide, ~1/1000 newborns have profound genetic deafness; China sees ~30k annual cases, OTOF 5–10%. Prior options: cochlear implants (~80% success but synaptic gap limits speech).

2026 updates: Expert consensus (Shu et al.) standardizes protocols; ARO 2026 highlights progress.

Challenges Ahead: Scaling and Broader Genes

• Large genes: Dual/triple vectors needed for MYO7A, USH1C.
• Age window: Best prelingual; older synaptic atrophy?
• Access: Cost, screening (China newborn genetic testing expanding).
• Regulation: China's NMPA fast-tracks; global harmonization via consensus.

Ongoing: Phase 3, multi-gene panels.

Impact on Patients and Society in China

Children now converse, attend mainstream schools—profound. Families report joy: one parent, "He hears my voice clearly." Economically, untreated deafness costs billions in special ed/lost productivity. Fudan's work aligns with equitable healthcare, reducing disparities.

Photo by Jannes Van den wouwer on Unsplash

Future Outlook: Towards Cure for All Genetic Deafness

Fudan plans expanded trials, combination therapies (gene edit + stem cells). Shu: "Gene therapy era for deafness dawns."Career advice for biotech aspirants: Fudan's model—interdisciplinary PhDs thrive here.

In summary, Fudan's breakthrough heralds curative era, showcasing Chinese higher ed's ascent. Explore higher ed jobs, university jobs, or China academic opportunities.