Global First-in-Class Dual-AAV Gene Therapy for OTOF-Related Deafness Nears BLA Submission as Companies Worldwide Advance Beyond AAV Packaging Limits
Regeneron
Biopharmaceutical Manufacturer
October 18, 2025
eMedClub News
Recently,Regeneron（Regeneron）Announced the publication of updated registrational CHORD trial data for its investigational dual-vector AAV gene therapy in the international top-tier medical journal, The New England Journal of Medicine, and at the American Academy of Otolaryngology–Head and Neck Surgery.（AAO-HNSF）Oral presentation at the annual meeting.
DB-OTO Utilizes a Dual AAV Vector Delivery Strategy, Packaging Different OTOF Gene Sequences Separately, which can re-form the complete OTOF gene within target cells through a specific mechanism to produce functional otoferlin. Moreover, the candidate product is characterized by exclusive cell-specificity.Myo15 Promoter Regulation, ensuring that the OTOF gene functions exclusively within the inner ear hair cells. Its administration is similar to cochlear implant surgery, being convenient and easy to promote, aiming to provide lasting, physiological auditory function for patients with congenital profound hearing loss caused by OTOF gene mutations.
In the CHORD trial, 12 subjects(10 months to 16 years)Of these, 9 received unilateral ear treatment and 3 received bilateral treatment.All 11 subjects showed improvement in hearing.. The trial met its primary endpoint, with 9 subjects undergoing behavioral pure-tone audiometry at week 24.（PTA）Assessed Hearing Level（dBHL）Threshold: ≤70 dB Hearing Level（dBHL）`, which corresponds to the clinical standard where cochlear implants are usually not required and natural acoustic hearing is achieved.`
It is worth noting that,Six subjects were able to hear whispered speech without assistive devices, and three subjects could even detect whispering.One subject who did not reach the primary PTA endpoint at 24 weeks showed an improvement in hearing sensitivity to "near-normal" levels at 48 weeks. In terms of safety, all 12 subjects tolerated both the surgical procedure and DB-OTO well, with no adverse reactions related to DB-OTO reported.
Lawrence R. Lustig, MD, Chair of Otolaryngology-Head and Neck Surgery at Columbia University Vagelos College of Physicians and Surgeons and study investigator, stated: "Previously, OTOF gene-related hereditary hearing loss was considered permanent. The data from this registration trial demonstrate consistent, rapid, and potent responses to DB-OTO; for patients with longer follow-up, we have observed not only stable hearing but also sustained improvement in speech understanding. For the families of these patients, these results carry even deeper significance."These mark the true entry of hearing loss treatment into a new era.。”
Currently, DB-OTO has received the FDA's Orphan Drug, Rare Pediatric Disease, Fast Track, and Regenerative Medicine Advanced Therapy designations. Regeneron plans to submit the BLA for DB-OTO later in 2025 after completing communications with the FDA. If all goes well,DB-OTO is expected to become the world's first potential FIC dual AAV gene therapy approved for the treatment of hereditary deafness., which is expected to drive the treatment landscape for hereditary deafness from auxiliary interventions towards a paradigm of fundamental cure.
Dual-vector AAV Gradually Verified, Promising Future Ahead
Regeneron's DB-OTO Breakthrough in the Field of Dual-Vector AAV Gene Therapy for Treating Hereditary Deafness Not Only Offers New Treatment Options for Patients with OTOF Gene Mutation-Related Deafness but Also Validates the Feasibility of the Dual-Vector Technology Pathway. Apart from Regeneron, Several Biopharmaceutical Companies Worldwide Have Also Invested in This Area. Overall, Most of the Current Dual-Vector AAV Gene Therapies Under Research Target OTOF Gene Mutation-Related Deafness, With a Small Number Expanding Into Other Indication Areas.
SensorionDeveloped a dual-vector AAV gene therapy, SENS-501. In July this year, Sensorion announced updated data from the Phase 1/2 clinical trial of SENS-501 for the treatment of OTOF gene mutation-related congenital deafness: the trial is divided into two dose cohorts, with three patients in each cohort.
A 11-month-old patient in the first cohort showed early signs of hearing improvement after 3 months of treatment.: Auditory Brainstem Response（ABR）Positive response occurred, with the optimal frequency reaching 70dB; pure-tone audiometry（PTA）Shows improvement in hearing levels within the speech frequency range; Meaningful Auditory Integration Scale for Infants and Toddlers（IT-MAIS）Score increased by 16 points(145% relative improvement from baseline)Through assessment, the child has reached the expected auditory developmental milestones corresponding to their age.
AK-OTOF byAkouosDeveloped by the company, October 2022,Eli LillyThe company invested approximately $610 million to acquire Akouos, aiming to accelerate the development of its hearing gene therapy. AK-OTOF utilizes AAVAnc80, a capsid with high transduction efficiency for inner hair cells, separately packaging nearly 6kb of human otoferlin cDNA and delivering it to the hair cells of the inner cochlea to replace the mutated gene, thereby restoring the function of inner ear cells. On January 23, 2024, Akouos announced preliminary clinical results from the AK-OTOF-101 study. In this study, the first 11-year-old patient who received gene therapy experienced full hearing recovery within 30 days after the AK-OTOF injection.
Stellar AscendIncubated and established in January 2022 by the Regeneron New Drug Fund, it is a biotechnology company focused on innovative drugs for inner ear hearing loss and related diseases. OTOV101 is a treatment for OTOF deafness developed by Star Otov.（DNFB9）The dual-vector gene therapy product, which is the result of technology transfer from Professor Renjie Chai's team at Southeast University.
Data presented at the 31st European Society of Gene and Cell Therapy Conference in 2024 showed that among 10 subjects, 3 received bilateral ear gene therapy. OTOV101 demonstrated good safety and tolerability, with a single cochlear injection quickly helping patients restore normal hearing.Three treated ears from two subjects(One patient received bilateral ear gene therapy)Followed up for more than 1 year, the efficacy persists, and the study will continue to follow up with the enrolled subjects for 5 years.
In July this year, Professor Chai Renjie, Chief Scientist of Xing Aotuowei, collaborated with multiple institutions in an international top-tier medical journalNature Medicine Published a research paper titled "AAV Gene Therapy for Autosomal Recessive Deafness 9: A Single-Arm Trial," reporting that AAV gene therapy demonstrated good long-term safety and efficacy in DFNB9 patients aged 1.5 to 23.9 years across different age groups, and revealing that the optimal intervention window may be between 5-8 years of age.
Dingxin GeneOne of the gene therapy companies in China that first adopted the AAV dual-vector delivery technology, its RRG-003, advanced in collaboration with the Eye, Ear, Nose, and Throat Hospital of Fudan University, is a dual AAV inner ear gene therapy targeting the OTOF gene. It employs a gene compensation approach, delivering RRG-003 to the cochlea through local minimally invasive administration to compensate for defective otoferlin. The results of its IIT study show,Four out of five patients showed significant improvement in hearing after receiving treatment, with good tolerability and safety.。
Weimei GeneIncubated by ShanghaiTech University, the company has developed novel AAV vectors with independent intellectual property rights for multiple organs such as the ear, eye, nose, and lung. Utilizing self-developed vectors across multiple pipelines, it is committed to developing next-generation gene therapies. In October this year, Dr. Cenfeng Chu, R&D head of Weimei Gene, delivered an oral presentation at the 32nd ESGCT meeting on the company's self-developed AAV-WM04 vector, which demonstrates higher infection efficiency compared to natural serotypes.Increase by More Than 10 Times, EA0010, an otic injection developed based on this platform, has been studied in investigator-initiated clinical trials, successfully restoring hearing in multiple patients while demonstrating good safety and tolerability.
In addition to deafness indications, ophthalmic indications are another direction with more players, such asAAVantgarde Bio、Prime Medicine, etc.
Summary
Overall, the dual-vector AAV technology pathway is being gradually validated, offering new therapeutic options for diseases caused by large-fragment gene mutations. Breaking through the limitations of single AAV delivery also signifies the shattering of the "capacity ceiling" in gene therapy, opening up imaginative space for treating a broader range of genetic disorders. In the future, with continuous technological advancements, the entire field of gene therapy is expected to move towards a new era of greater precision, higher efficiency, and wider accessibility.
Editor-in-Chief | Xun
Proofread by Xun
References:
1.https://investor.regeneron.com/news-releases/news-release-details/db-oto-results-new-england-journal-medicine-showcase-dramatic
2. Corporate Official Website
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