The abnormality of vestibular hair cells and the gene transduction in animal model of human genetic inner ear disease - Study of vestibular hair cell pathology in shaker-2 mouse and waltzing guinea pig

We reviewed the hair cell pathology of genetic hearing loss and circling behavior and discussed possibility of gene therapy in human genetic inner ear disease through genetic inner ear disease animal models. First, we focused on the cytocauds containing pathological actin filaments in the vestibular type 1 hair cell of waltzing guinea pigs (WGP) and in auditory and vestibular hair cells of shaker-2 mice. The cytocaud, which seems like to be an actin filaments ladder, penetrates the basement membrane and runs along nerve fiber. One possible explanation is that hair cells detach from the basement membrane during development but do not in WGP and shaker-2 mice. However, the molecular signals that are required for detachment are unknown. Furthermore, we tested the possibility of gene transudation in shaker-2 mice, the model of DFNB3, i.e. human deafness, in order to treat the hair cell pathology including cytocaud. Vestibular sensory epithelia of explant organ culture obtained from mouse pups at P1, P3, and P5 were transfected by adenovirus vector containing the bacterial lacZ in vitro and processed to detect the reporter gene expression. Vestibular hair cells can be transduced at all stages in shaker-2 mice. Our data demonstrate that differentiating hair cells in mouse explants can be virally transduced, suggesting that wild-type genes can be inserted into these cells to correct the phenotype. We need further investigations of gene therapy using animal in vivo data to discuss the possibility of clinical application for the genetic inner ear diseases.