Delivery of the gene encoding X-linked inhibitor of apoptosis
) using an adeno-associated viral (AAV) vector can protect against 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
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
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.
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.