Developmental research of the gene therapy which is targeted embryonic inner ear for congenital inner ear disease

Abstract

　Genetic defects are a major cause of hearing loss in newborns. Numerous causative genes for genetic hearing loss have been identified. Most genes cause only hearing loss which is referred to as non-syndromic deafness. On the other hand, some genes cause not only congenital hearing loss but also vestibular dysfunction, etc., which is referred to as syndromic deafness. However, presently, there are no truly curative treatments for this condition. One of the feasible treatments for congenital inner ear disease is “gene therapy during the embryonic stages” before the expression of abnormal morphology and function of the inner ear. In 2008, Gubbles et al. reported on gene transfer by transuterine-mediated injection into the embryonic inner ear (otocyst) and electroporation at embryonic day 11.5 (E11.5). We also utilized those methods, and performed electroporation-mediated transuterine gene transfer into otocysts (EUGO) for two models of congenital inner ear disease. One is the Connexin (Cx) 30 knockout (KO) mouse in which GJB6 gene coding Cx30 is deleted. The other is the pendrin KO mouse in which the SLC26A4 gene coding pendrin is deleted. The former is the model of non-syndromic deafness, the latter is the model of syndromic deafness. EUGO caused the vast expression of normal genes in the inner ear and successfully improved the hearing and vestibular function in both models. Although we utilized the otocyst at E11.5, this method must be demonstrated before the beginning of gene expression in the inner ear. Thus, the timing of embryonic gene therapy is important, because each gene has a different timing of expression in the inner ear. Herein, we describe state-of-the-art research on genetic inner ear disease treatment through gene therapy and discuss the obstacles to overcome in curative treatments of genetic inner ear diseases in humans.