“AAV1-HOTOF Gene Therapy for Autosomal Recessive Deafness 9: a Single-Arm Trial”, 2024-01-24 ():
Evidence before this study: We searched PubMed from inception to Oct 1, 2023, for all studies in English on OTOF mutations, their associations with congenital hearing loss, including autosomal recessive deafness 9 (DFNB9), and all related animal preclinical and human clinical trials. The search terms included “OTOF”, “DFNB9”, “hereditary hearing loss”, “gene therapy”, “DFNB9 trial”, “DFNB9 mouse”, or combinations thereof. We also searched ClinicalTrials.gov for related clinical trials. We found proof-of-principle of gene therapy for DFNB9 in animal models using recombinant adeno-associated viral vectors and 4 clinical trials. We found no reports on the safety or efficacy of human gene therapy to treat DFNB9.
Added value of this study: To our knowledge, this study is the first prospectively registered and the first-in-human clinical trial with the largest number of patients and the longest follow-up published to date of gene therapy targeting OTOF to treat autosomal recessive deafness 9. These data indicate that adeno-associated virus (AAV) administration in the human inner ear is safe and efficacious in treating genetic hearing loss. The study extends the utility of dual AAV to overcome the gene size limit to treat human diseases.
Implications of all the available evidence: Our study provides evidence of the safety and efficacy of gene therapy to treat autosomal recessive deafness 9 and lays a foundation for gene therapy as a novel treatment for other forms of genetic hearing loss. The process and techniques developed in this study are likely to advance the field of gene therapy for hearing loss.
Background: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.
Method: This single-arm, single-centre trial enrolled children (aged 1–18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing.
Results: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled 6 children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and 5 received 1.5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1–2 and two (4%) were grade 3 (decreased neutrophil count in one participant). 5 children had hearing recovery, shown by a 40–57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0.5–4.0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1.5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in 4 children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery.
Interpretation: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9.
Funding: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.