Auditory Improvements Seen in First Child Treated With OTOF Hearing Loss Gene Therapy


Other efforts to develop a gene therapy for OTOF congenital hearing loss include programs from Sensorion and Eli Lilly.

The first child with otoferlin (OTOF)-related hearing loss treated with gene therapy DB-OTO in the phase 1/2 CHORD clinical trial (NCT05788536) has shown some improvements in auditory responses.1

Professor Manohar Bance, MB

Professor Manohar Bance, MB

“The children who are being enrolled in CHORD are often born with profound hearing loss due to mutations in a single gene, OTOF, which essentially turns off their auditory circuits,” Professor Manohar Bance, MB, ear surgeon and principal trial investigator, Cambridge University Hospitals NHS Foundation Trust, United Kingdom (UK), said in a statement.1 “Cochlear implants are the current standard of care but are unable to replicate the full complexity and range of sound. With these very preliminary DB-OTO results, we now have encouraging evidence that this gene therapy may be able to help turn these auditory circuits back on. We look forward to following this child and others further to determine if DB-OTO gene therapy can restore clinically meaningful hearing as they are learning to interact with the world.”

The child, who is less than 2 years of age, received an intracochlear injection of DB-OTO in 1 ear. Investigators found that the child experienced improvements in auditory brainstem response (ABR) and behavioral (pure tone) audiometry through 6 weeks of follow-up as compared to baseline. ABR is often absent in people with OTOF-related hearing loss and was absent in both ears of the treated child at baseline. Investigators did not observe anyconcerning safety signals through week 6 following treatment.

DB-OTO is an investigational cell-selective, adeno-associated virus (AAV) gene therapy designed to deliver a working copy of OTOF via an intracochlear injection under general anesthesia. The vector also delivers a proprietary cell-specific Myo15 promoter intended to restrict expression only to the cells that normally express otoferlin. DB-OTO has been granted rare pediatric disease designation from the FDA and orphan drug designation from the FDA and European Medicines Agency. The program was originally developed under a collaboration between Regeneron and Decibel Therapeutics and moved wholly under Regeneron’s purview when the company acquired Decibel in September 2023. Regeneron is also investigating the AAV.103 program for people with GJB2-related hearing loss and the AAV.104 program for people with stereocilin-related hearing loss.

READ MORE: CSF Infusion of Gene Therapy Transduces Cochlear Cells

The first-in-human, multicenter, open-label CHORD trial is evaluating the safety, tolerability, and preliminary efficacy of DB-OTO in pediatric patients with congenital hearing loss due to OTOF mutations. The trial is enrolling children across sites in the US, UK, and Spain for a 2-part study, the first of which will administer dose levels of DB-OTO to a single ear and the second of which will administer a selected dose to both ears.

Clinical Takeaways

  • The first child with OTOF-related hearing loss treated with gene therapy DB-OTO in the CHORD clinical trial showed promising improvements in auditory responses.
  • DB-OTO, an investigational gene therapy, was well-tolerated in the treated child, with no concerning safety signals observed through six weeks post-treatment.
  • OTOF-related hearing loss is an ultra-rare condition with no approved pharmacologic treatments. Other causes of congenital hearing loss are potentially easy targets for other gene therapies.

“These preliminary DB-OTO results provide early and encouraging proof-of-concept for the treatment of otoferlin-related hearing loss, as well as our pipeline of gene therapies to address more common forms of genetic hearing loss and other therapeutic areas,” Christos Kyratsous, PhD, senior vice president, research and cohead, genetic medicines, Regeneron, added.1 “The ongoing CHORD trial is our first clinical-stage auditory program, and we are incredibly grateful to the investigators and the family of this child for embarking on this breakthrough trial. We remain committed to advancing this research and hope these results mean that children with genetic hearing loss will eventually be able to benefit from the revolutionary promise of gene therapies like DB-OTO.”

OTOF-related hearing loss is an ultra-rare cause of congenital hearing loss, all forms of which have no approved pharmacologic treatment options. Most causes of permanent, congenital hearing loss in developed countries are sensorineural and result from a single gene defect, making them potential targets for gene therapy.

Despite the ultra-rare incidence of OTOF-related hearing loss, other companies are seeking to develop their own gene therapies for the same indication. Sensorion's OTOF-GT differs from Regeneron’s product as it contains a dual AAV vector for assembly in place of OTOF. The company submitted a clinical trial application to conduct the phase 1/2 Audiogene clinical trial in the UK in children less than 31 months of age.2 Eli Lilly 's AK-OTOF, also an investigational dual AAV vector-based gene therapy is being evaluated in a phase 1/2 clinical trial (NCT05821959) in patients aged 2 to 17 years with biallelic mutations in OTOF and profound bilateral sensorineural hearing loss at the Children's Hospital of Philadelphia.3

1. Regeneron shares preliminary results showing gene therapy improves auditory responses in child with profound genetic hearing loss. News release. Regeneron. October 26, 2023.
2. Sensorion submits clinical trial application for lead gene therapy candidate OTOF-GT in the UK. News release. Sensorion. July 10, 2023. Accessed July 11, 2023.
3. Lilly completes acquisition of Akouos expanding efforts to help people with genetic diseases. News release. Eli Lilly and Company. December 1, 2022. Accessed July 11, 2023.
Related Videos
Faraz Ali, MBA, the chief executive officer of Tenaya Therapeutics
Evan Weber, PhD, an assistant professor of pediatrics at Children's Hospital of Philadelphia
Faraz Ali, MBA, the chief executive officer of Tenaya Therapeutics
Shankar Ramaswamy, MD, the cofounder, chairman, and CEO of Kriya Therapeutics
Kevin Campbell, PhD, a Howard Hughes Investigator at the University of Iowa
Debora Mazzetti, MS, on Multitargeting MicroRNA in Glioblastoma
Abhishek Gupta, BS, the senior vice president of genetic medicines at Syneos Health
Francesca Del Bufalo, MD, PhD, a medical doctor and scientist at Bambino Gesù Chidren’s Hospital
Luke Roberts, MBBS, PhD, on Early Clinical Data on Congestive Heart Failure Gene Therapy
Lawrence R. Lustig, MD, the chair of the Department of Otolaryngology—Head and Neck Surgery at Columbia University College of Physicians
© 2024 MJH Life Sciences

All rights reserved.