AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity

Louis B. Cooper, Dylan K. Chan, Frederick C. Roediger, Brian R. Shaffer, Justin F. Fraser, Sergei Musatov, Samuel H. Selesnick, Michael G. Kaplitt

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish
Pages (from-to)484-490
Number of pages7
JournalOtology and Neurotology
Volume27
Issue number4
DOIs
StatePublished - Jun 2006

Keywords

  • Adeno
  • Apoptosis
  • Associated virus
  • Caspase
  • Cisplatin
  • Gene therapy
  • XIAP

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Sensory Systems
  • Clinical Neurology

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