Decibel Therapeutics' Gene Therapy Strategies To Restore Hearing And Balance
By Erin Harris, Editor-In-Chief, Cell & Gene
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Decibel Therapeutics is a Boston-based, clinical-stage biotech dedicated to discovering and developing transformative new medicines for hearing and balance disorders, one of the largest areas of unmet need in medicine. The company’s lead gene therapy product candidate is DB-OTO, a cell-selective, adeno-associated virus (AAV) product candidate designed to provide durable, physiological hearing in individuals with hearing loss caused by mutations of the otoferlin (OTOF) gene. I caught up with Decibel’s CEO and President, Laurence Reid, Ph.D. to learn more about gene therapy as a modality for the ear, the state of the clinical trial, and more.
Briefly describe Decibel Therapeutics.
We aim to restore and improve hearing and balance through the restoration and regeneration of functional hair cells and non-sensory support cells within the inner ear. Our clinical and preclinical gene therapy programs are designed to selectively replace genes for the treatment of congenital, monogenic hearing loss and to regenerate inner ear hair cells for the treatment of acquired hearing and balance disorders.
Our lead gene therapy product candidate is DB-OTO, a cell-selective, AAV product candidate designed to provide durable, physiological hearing in individuals with profound, congenital hearing loss caused by mutations of the otoferlin (OTOF) gene. The OTOF protein is expressed in cochlear inner hair cells and enables communication between the sensory hair cells of the inner ear and the auditory nerve. Newborns with biallelic OTOF mutations have fully developed structures within the inner ear but have profound hearing loss because signaling between the ear and the brain is disrupted.
We are focused on both hearing loss and balance disorders due to their widespread impact and shared biology. Hearing loss is one of the largest areas of unmet need in medicine, and per WHO estimates, affects hundreds of millions of people worldwide. Hearing loss can significantly impact mental health, cognition, and language development. Beyond hearing loss, dysfunction of the inner ear can lead to severe impairments in balance. Balance problems can lead to significant life impairment and an increased risk of falls, potentially resulting in hospitalization, limited mobility, and depression. Despite these impacts, there are no approved therapies for the treatment of hearing loss or balance disorders.
Why is gene therapy a strong modality for the ear and for people with hearing and balance disorders?
We believe AAV gene therapy is an ideal modality for the ear because the inner ear is a small, enclosed compartment. This anatomy provides the opportunity for local delivery of high vector concentrations, which may increase transgene expression in the target cell type, limit systemic exposure to improve safety and reduce the quantity of AAV drug product needed. Additionally, inner ear hair cells are non-dividing, which means that AAV vector genomes are not diluted, eliminating a hurdle for achieving durable expression following a single administration of AAV gene therapy.
Explain Decibel's platform and the use/need for AAV.
We believe the lack of approved therapies is caused in part by the complex biology of the inner ear, and we have built our platform to overcome this challenge. We apply proprietary analyses of gene expression in the inner ear to generate a comprehensive database of the molecular constitution of all relevant inner ear cell types. Our capabilities include epigenetic capabilities to sequence regions of active DNA within cells, transcriptomic capabilities to characterize cell function and capabilities to enable identification of alternative transcript splicing. Our database currently includes over three million cellular gene expression profiles from several mammalian species.
We are using this dataset to identify and select targets, including reprogramming factors to promote inner ear hair cell regeneration, and cell-selective promoters to drive precise expression of transgenes that are intended to restore functionality in hair cells and non-sensory support cells of the inner ear. Cell-selective regulation of transgenes is an important part of our strategy, and to date, we have generated and confirmed the specificity of cell-selective promoters that limit expression to several therapeutically relevant inner ear cells in mice and non-human primates.
Explain the status of the DB-OTO clinical trial.
Our DB-OTO Phase 1/2 clinical trial is called CHORDTM. The CHORD trial is part of an international regulatory strategy for the clinical development of DB-OTO, which includes regulatory clearance to conduct studies in the U.S., U.K., and Spain.
As referenced above, one of the reasons that we chose to pursue OTOF related hearing loss is because newborns with biallelic OTOF mutations have developed structures within the inner ear, suggesting that the sensory cells within the inner ear may remain viable and that expression of a functional OTOF gene could enable restoration of hearing. We expect that the first two patients in the U.S. will be as young as seven years of age and that participants in the U.K. and Spain will be infants two years of age and younger, providing the ability to evaluate DB-OTO in a range of pediatric ages.
In addition to evaluating safety and tolerability, the clinical trial will employ auditory brainstem response (ABR) and age-appropriate behavioral measurements of hearing as efficacy endpoints. ABR is a clinically established, objective, physiologic measure of hearing sensitivity that is routinely used in newborn testing and diagnosis. Individuals with otoferlin-related deafness have no detectable ABR, and therefore this endpoint will serve as an early readout of DB-OTO’s impact on hearing functionality and sensitivity. We currently have active clinical trial sites in the U.S., U.K., and Spain.
What are Decibel's anticipated milestones?
Regarding DB-OTO, we anticipate reporting the initial safety and tolerability data and preliminary efficacy data, as measured by ABR, from the first patients in the Phase 1/2 clinical trial in the first quarter of 2024.
Share additional information Cell & Gene's audience should understand regarding gene therapy for the ear.
One final potential benefit conferred by the inner ear is that our intended delivery route utilizes the same surgical approach currently used by neurotologists and pediatric otolaryngologists during a standard cochlear implantation procedure. The approach is referred to as transmastoid and is used to access the round window membrane into the inner ear, through which DB-OTO will be infused directly into the cochlea. We selected this approach based on feedback from a surgical advisory board based on our plan to deliver DB-OTO to pediatric patients.