Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry

Area of Science:

• Neuroscience
• Genetics
• Otolaryngology

Background:

• Biallelic variants in the CABP2 gene cause non-syndromic hearing loss (DFNB93) by affecting inner hair cell (IHC) synaptic function.
• DFNB93 is classified as auditory synaptopathy, a hearing disorder resulting from impaired IHC synapses.

Purpose of the Study:

• To review preclinical gene replacement studies for hereditary hearing loss.
• To highlight CABP2 as a promising candidate gene for virus-mediated gene therapy to restore hearing.
• To outline characteristics of ideal genetic targets for therapy development.

Main Methods:

• Review of current literature on human CABP2 studies and preclinical therapy development.
• Analysis of DFNB93 mouse models to understand the role of CaBP2 in synaptic sound encoding.
• Examination of otoacoustic emissions in affected families to assess outer hair cell function.

Main Results:

• Lack of CaBP2 in DFNB93 mouse models impairs synaptic sound encoding due to enhanced inactivation of CaV1.3 Ca2+ channels.
• Preclinical studies demonstrate the feasibility of gene therapy for DFNB93.
• Evidence suggests CABP2 gene therapy is a viable strategy for hearing restoration in auditory synaptopathies.

Conclusions:

• CABP2 gene therapy holds significant potential for treating DFNB93 hereditary hearing loss.
• Auditory synaptopathies are promising therapeutic targets for hearing restoration, as supported by OTOF gene trials.
• A patient registry is introduced to facilitate research involvement and advance towards CABP2 gene therapy clinical trials.