AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity.
| Publication Type | Academic Article |
| Authors | Cooper L, Chan D, Roediger F, Shaffer B, Fraser J, Musatov S, Selesnick S, Kaplitt M |
| Journal | Otol Neurotol |
| Volume | 27 |
| Issue | 4 |
| Pagination | 484-90 |
| Date Published | 06/01/2006 |
| ISSN | 1531-7129 |
| Keywords | Antineoplastic Agents, Auditory Threshold, Caspase Inhibitors, Cisplatin, Hearing Loss, Sensorineural, X-Linked Inhibitor of Apoptosis Protein |
| Abstract | HYPOTHESIS: Delivery of the gene encoding X-linked inhibitor of apoptosis (XIAP) using an adeno-associated viral (AAV) vector can protect against cisplatin-mediated ototoxicity. BACKGROUND: Cisplatin is a widely used chemotherapeutic agent with significant ototoxic side effects. One possible mechanism of toxicity is apoptotic death of many cochlear cell types. Acute treatment with inhibitors of caspases- enzymes critical for apoptosis- has been shown to prevent hearing loss in vivo, but is too short-acting for therapeutic use. Gene therapy provides a specific and chronic means of delivering potential therapeutic gents. Introducing an anti-apoptotic gene into the cochlea could provide long-term prophylaxis against the ototoxic effects of cisplatin. METHOD: Two groups of rats were treated with unilateral injection into the round window of AAV harboring a gene encoding either XIAP or green fluorescent protein (GFP). After at least two months of gene expression, auditory-brainstem-response (ABR) threshold shifts and outer-hair-cell (OHC) number were measured in these two groups of animals after 72-hour treatment with cisplatin. RESULTS: Consistent with previous reports, uninjected and AAV.GFP-injected ears displayed profound ABR threshold elevations and OHC loss after cisplatin treatment. Ears that had been injected with AAV encoding XIAP, however, were significantly protected from these effects: cisplatin-induced ABR-threshold shift and hair-cell loss were attenuated by as much as 78% and 45%, respectively, when compared with contralateral (untreated) ears. CONCLUSION: XIAP delivery to the cochlea can protect against the audiometric changes and hair-cell loss associated with cisplatin ototoxicity. The efficacy, specificity, and duration of the protective effects make this a potentially attractive therapeutic paradigm. |
| DOI | 10.1097/01.mao.0000202647.19355.6a |
| PubMed ID | 16791039 |