Learning Objectives: Hearing loss is the most widespread sensory disorder, with an incidence of congenital genetic deafness of 1 in 1,600 children. For many ethnic populations, the most prevalent form of genetic deafness is caused by recessive mutations in the gene gap junction protein, beta 2, 26 kDa (GJB2), which is also known as connexin 26 (Cx26). For more than 15 years, we have developed and evaluated a mouse model of Gjb2-related deafness as follows, i) a dominant-negative Gjb2 R75W transgenic mouse model shows incomplete development of the cochlear supporting cells, resulting in profound deafness from birth (Kudo et al., Hum Mol Genet 2003; Inoshita et al., Neuroscience 2008), ii) the outer hair cells (OHCs from the dominant-negative mutation of Gjb2 are deformed, but reveal normal development and maturation (Minekawa et al. , Neuroscience 2009), iii) Cx26 dysfunction is associated with delayed apoptosis and retention of the greater epithelial ridge cells (Inoshita et al., BMC Genet 2014), iv) the disruption of the cochlear gap junction plaques is associated with the Gjb2-related deafness and the the assembly of cochlear gap junction plaques is dependent on Cx26 (Kamiya et al., J Clin Invest 2014), vi) the deformation of OHCs and the accumulation of caveolin-2 in the organ of Corti plays a crucial role in the progression of, or secondary OHC loss in, Gjb2-associated deafness (Anzai et al., Plos One 2015). In the next, we focused on the development of fundamental therapies for Gjb2-related deafness. Successful transgene expression was obtained through the round window membrane in the supporting cells of the neonatal mouse cochlea using adeno-associated viral (AAV) vectors without causing additional damage to the cochlear function (Iizuka et al., Huma Gen Ther 2008). Perinatal cochlear delivery of Gjb2 using an AAV significantly improved the auditory responses and development of the cochlear structure (Iizuka et al., Hum Mol Genet 2015).
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