title: 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%.
authors: Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China.
authors: H
authors: H
authors: Jie
authors: Department of Physiology, Medical College, Southeast University, Nanjing, China.
authors: S
authors: S
authors: Tao
authors: Department of Physiology, Medical College, Southeast University, Nanjing, China.
authors: L
authors: L
authors: Liu
authors: Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China.
authors: L
authors: L
authors: Xia
authors: School of Human Communication Disorder, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: A
authors: A
authors: Charko
authors: School of Human Communication Disorder, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Z
authors: Z
authors: Yu
authors: Department of Surgery, Division of Otolaryngology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: M
authors: M
authors: Bance
authors: Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China.
authors: S
authors: S
authors: Yin
authors: Departments of Psychiatry and Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: G S
authors: GS
authors: Robertson
authors: 1] Department of Otolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China [2] School of Human Communication Disorder, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: J
authors: 0000000336336799
authors: J
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000378:metabolism; D034381:Hearing Loss / Q000139:chemically induced* / Q000517:prevention & control*; D012405:Round Window, Ear / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; D002945:Cisplatin