gms | German Medical Science

To date, the clinical treatment of auditory synaptopathies, as well as other genetic hearing disorders, involves the use of hearing aids or, in severe cases, cochlear implants. However, future gene therapies promise to restore hearing in selected forms of monogenic hearing disorders where the morphology of the cochlea is preserved in a time window that allows function to be restored. For the very first time, the feasibility of gene therapy in patients suffering from the genetic hearing disorder DFNB9 has been demonstrated in clinical trials. Other targets for gene therapy include the non-syndromic autosomal recessive hearing impairment DFNB93, which is caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of the voltage-gated calcium channels Ca_V1.3 of the inner hair cells (IHC). Based on phenotype of the Cabp2^-/-mice, DFNB93 hearing impairment was attributed to increased steady-state inactivation of inner hair cell Ca_V1.3 channels, effectively limiting their availability to trigger synaptic transmission. However, this does not appear to affect cochlear development and does not lead to early degeneration of hair cells or their synapses. A proof-of-concept study demonstrated the potential of a gene therapy approach for the treatment of DFNB93. AAV-mediated replacement of Cabp2 in early postnatal Cabp2^-/- mice restored Ca_V1.3 function of the IHCs, leading to an improvement in hearing (Oestreicher et. al, 2021). This was also shown in mice that lack the two most abundantly expressed IHC CaBPs, Cabp1/2-DKO-mice (Oestreicher et. al, 2024). Since hearing impairment in the apical region of the cochlea could be restored better than in the high-frequency basal region of the cochlea with possibly different IHC synaptic calcium handling, we additionally investigated a strategy in which the calcium-binding properties of CaBP2 were altered to exclude a possible negative effect of the calcium-buffering properties of the (overexpressed) protein in the IHCs. For this purpose, we employed in vitro and in vivo measurements and characterized the amount of hearing rescue after AAV-mediated gene transfer of Cabp2 lacking the calcium binding.