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


METHODS
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.


CONCLUSIONS
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.
Cooper
Louis B
LB
Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.
Chan
Dylan K
DK
Roediger
Frederick C
FC
Shaffer
Brian R
BR
Fraser
Justin F
JF
Musatov
Sergei
S
Selesnick
Samuel H
SH
Kaplitt
Michael G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001300:Audiometry, Evoked Response; D001309:Auditory Threshold / Q000187:drug effects*; D061945:Caspase Inhibitors; D002945:Cisplatin / Q000633:toxicity*; D000229:Dependovirus; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000235:genetics; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008856:Microscopy, Fluorescence; D015999:Multivariate Analysis; D010865:Pilot Projects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000008:administration & dosage* / Q000235:genetics
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D051636:X-Linked Inhibitor of Apoptosis Protein; D049452:Green Fluorescent Proteins; D002945:Cisplatin