Gene Therapy for Congenital Hearing Loss Granted Orphan Drug, Rare Pediatric Disease Designations


Decibel Therapeutics previously presented favorable preclinical data at ASGCT 2021.

The FDA has granted orphan drug and rare pediatric disease designations to Decibel Therapeutics’ DB-OTO for the potential treatment of otoferlin-related congenital hearing loss (CHL).1

The dual-vector adeno-associated virus (AAV) investigational gene therapy is being developed in collaboration with Regeneron Pharmaceuticals as a part of the companies’ partnership. The therapy, which uses a proprietary, cell-selective promotor to control gene expression in cochlear hair cells, is designed to restore hearing to patients with CHL due to mutations in the otoferlin gene.

“We are pleased to receive these important designations from the FDA, which support our conviction that innovative treatments for congenital hearing loss are urgently needed,” said Heather Wolff, vice president, clinical development operations, Decibel, in a statement.1 “Preclinical studies support the potential of DB-OTO to provide hearing to children born with profound hearing loss due to a mutation of the otoferlin gene. We are looking forward to initiating a Phase 1/2 clinical trial of DB-OTO in pediatric patients in 2022.”

DB-OTO is currently in preclinical studies, data from which were presented at the 24th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), May 12-15.2 The research presented demonstrated DB-OTO's pharmacological modulation of otoferlin expression and durable functional rescue in mice as measured by the Auditory Brainstem Response. 

READ MORE: Orphan Drug Designation Granted to Bietti's Crystalline Dystrophy Gene Therapy

“Of the 1 in 500 neonates who are born with hearing loss annually in the US, 50 to 200 are caused by Otoferlin deficiency. There are no approved therapies for Otoferlin deficiency; infants with biallelic OTOF mutations are currently managed with assistive devices,” first author Adam Palermo, PhD, vice president, molecular platform, Decibel, and colleagues wrote.2

The study also demonstrated favorable safety findings in mice. To restrict transgene expression and prevent dose-limiting toxicities, investigators developed a surgical delivery approach translatable into routine otolaryngological practice. The approach uses slow AAV infusion through the round window membrane and vestibular fenestration to allow egress of displaced perilymph by the therapy. The investigators believe this approach can be used in the clinic, with Decibel expecting to initiate clinical testing in 2022.

“DB-OTO is a promising emerging therapeutic for genetic hearing loss and has the potential to provide the first clinical proof-of-concept for gene therapy in the inner ear,” Palermo and colleagues concluded.2

In addition to DB-OTO, Decibel Therapeutics has another gene therapy candidate in preclinical studies for the treatment of bilateral vestibulopathy (BV). The therapy is designed to restore balance by regenerating lost hair cells within the vestibule. Other gene therapy products addressing hearing loss and BV are in earlier discovery phases.

Otonomy, another company exploring gene therapies for the treatment of CGL, also presented favorable preclinical data at ASGCT 2021 on their OTO-825 candidate.3 Their data showed that OTO-825 reduced hearing loss and repaired structural damage in the inner ear in 2 mouse models.

“Based on these encouraging results that demonstrate hearing recovery and improved cochlear morphology following OTO-825 administration, the companies have initiated IND-enabling activities and look forward to providing additional details of the program in the next several months,” Alan C. Foster, PhD, chief scientific officer, Otonomy, said in a statement at that time.3

1. Decibel Therapeutics receives orphan drug and rare pediatric disease designations for DB-OTO for the treatment of otoferlin-related congenital hearing loss. News release. Decibel Therapeutics. September 9, 2021.
2. Palermo A, Zhang X, Senapati A, et al. Development of an AAV-based gene therapy for children with congenital hearing loss due to otoferlin deficiency (DB-OTO). Presented at 2021 American Society of Gene & Cell Therapy; May 12-15. Abstract 579.
3. Otonomy and AGTC to Present Preclinical Proof-of-Concept Results for OTO-825 Gene Therapy at ASGCT Annual Meeting. News release. Otonomy. April 28, 2021. Accessed September 9, 2021.
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