Cochlear protection against cisplatin by viral transfection of X-linked inhibitor of apoptosis protein across round window membrane.

ABSTRACT

We have previously demonstrated that both age-related and noise-induced hearing loss are reduced in transgenic mice that ubiquitously overexpress X-linked inhibitor of apoptosis protein (XIAP). In view of the therapeutic implications of these findings, we have developed a minimally invasive surgical method to deliver adenoid-associated virus (AAV) across the round window membrane (RWM) of the cochlea, enabling efficient gene transfer to hair cells and sensory neurons in this enclosed structure. This RWM approach was used in the present study to evaluate the effectiveness of AAV-mediated XIAP overexpression in protecting against cisplatin-induced ototoxicity. Two weeks following surgery, AAV-derived XIAP was detected in the majority of inner and outer hair cells, resulting in a threefold elevation of this antiapoptotic protein in the cochlea. The protection of AAV-mediated XIAP overexpression was evaluated in animals treated with cisplatin at a dose of 4 mg kg(-1) per day for 4-7 consecutive days. The XIAP overexpression was found to attenuate cisplatin-induced hearing loss by ~22 dB. This was accompanied by a reduction of the loss of vulnerable hair cells and sensory neurons in the cochlea by 13%.