AAV-based gene therapy partially rescues hearing in a DFNB93 mouse model

With recent advances in the field of gene therapeutics, gene therapy to target monogenetic hearing impairment promises to be a selective treatment option offering better, close to normal hearing performance, than currently used hearing aids or cochlea implants. AAV-based gene therapeutic approaches have already shown efficient restoration of hearing in mouse models, e.g. DFNA25, DFNA36 and DFNB9.

Another gene-therapy target could be non-syndromic autosomal recessive hearing impairment DFNB93. This is caused by defects in the CABP2 gene, coding for Calcium-binding protein 2 (CaBP2), which acts as a strong modifier of voltage-gated calcium channels Ca_V1.3 in the inner hair cells (IHCs).

DFNB93 disease modeling in mice revealed enhanced steady-state inactivation of IHC Ca_V1.3 channels, which limits the amount of activatable channels to trigger synaptic transmission. Here, we compared the potential of two AAV variants, AAV2/1 and synthetic AAV-PHP.eB, for the treatment of DFNB93. Both viral vectors contained the Cabp2 coding sequence to restore Cabp2 expression in IHCs of early postnatal Cabp2 < sup>-/- </sup > mice. We used both in vitro and in vivo techniques to assess the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca_V1.3 function resulting in improved hearing of Cabp2 < sup>-/- </sup>mice. This preclinical study proves the feasibility of DFNB93 gene therapy.

Publication History

Article published online:
24 May 2022