title: Therapeutic regulation of gene expression in the inner ear using RNA interference.
abstract: Targeting and downregulating specific genes with antisense and decoy oligonucleotides, ribozymes or RNA interference (RNAi) offer the theoretical potential of altering a disease phenotype. Here we review the molecular mechanism behind the in vivo application of RNAi-mediated gene silencing, focusing on its application to the inner ear. RNAi is a physiological phenomenon in which small, double-stranded RNA molecules (small interfering RNA, siRNA) reduce expression of homologous genes. Notable for its exquisite sequence specificity, it is ideally applied to diseases caused by a gain-of-function mechanism of action. Types of deafness in which gain-of-function mutations are observed include DFNA2 (KCNQ4), DFNA3 (GJB2) and DFNA5 (DFNA5). Several strategies can be used to deliver siRNA into the inner ear, including cationic liposomes, adeno-associated and lentiviral vectors, and adenoviral vectors. Transduction efficiency with cationic liposomes is low and the effect is transient; with adeno-associated and lentiviral vectors, long-term transfection is possible using a small hairpin RNA expression cassette.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Maeda
authors.forename: Abraham M
authors.initials: AM
authors.lastname: Sheffield
authors.forename: Richard J H
authors.initials: RJH
authors.lastname: Smith
mesh_terms: D000818:Animals; D003052:Cochlear Aqueduct / Q000502:physiology; D000072259:Connexin 26; D017630:Connexins; D005786:Gene Expression Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics; D007759:Labyrinth Diseases / Q000628:therapy*; D020320:Oligoribonucleotides, Antisense / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D016337:RNA, Catalytic / Q000502:physiology; D014162:Transfection
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D020320:Oligoribonucleotides, Antisense; D016337:RNA, Catalytic; C427204:hammerhead ribozyme; D000072259:Connexin 26