**8. Summary and perspective**

312 Hearing Loss

participate in and/or regulate the docking and membrane fusion of post-Golgi vesicles to the plasma membrane at the PRC. Therefore, the USH2 complex at the PMC might play either a direct or indirect role in the docking between the post-Golgi vesicles and plasma membrane at the base of the connecting cilium (Roepman and Wolfrum, 2007; Maerker et al., 2008). This proposed function can also be applied in hair cells. The ankle-links exist when stereocilia grow and differentiate from small microvilli. At this time, many vesicles are at the base of stereocilia (Forge et al., 1997; Hasson et al., 1997), which could be the post-Golgi vesicles carrying proteins and membrane lipids from the cell body to the growing stereocilia. Supportively, the *Gpr98* knockout mouse shows delocalization of some CDH23 long isoforms at the tip of the stereocilia and, possibly, loss of some apical links between the stereocilia (Michalski et al., 2007). However, solid evidence supporting this putative function of the USH2 complex is still scarce. For instance, obvious mislocalization of rhodopsin has not been observed in whirlin knockout and *Ush2a* knockout mice (Liu et al., 2007; Yang et al., 2010), and vesicles fused with the plasma membrane have not been

Because of the widespread clinical application of the well-developed cochlear implant for hearing loss (Pennings et al., 2006; Liu et al., 2008), more attention is focused on seeking effective treatments for retinitis pigmentosa in USH. Next, I will address the current progress in studies on gene therapy, drug application, cell transplantation, and nutritional

Human neural progenitor cells from the post mortem fetal cortical brain have been tested in the *Ush2*a knockout mouse (Lu et al., 2009). The progenitor cells were transplanted between photoreceptors and RPE cells. There, they delayed the cellular changes in photoreceptors and alleviated retinal functional deterioration. However, due to the short follow-up time after the treatment, the study did not examine whether the treatment can rescue

Compared to the cell-based therapy, replacement of the mutant gene in the retina is straightforward. The efficiency and efficacy of a lentivirus-mediated gene replacement of MYO7A have been studied in the *Myo7a4626SB* mouse (Hashimoto et al., 2007). Although the delivery of MYO7A into photoreceptors and RPE cells is not quite efficient, the treated mutant retina does show correction of the histological phenotypes in these two cells. In addition, our laboratory utilized a combination of AAV and a photoreceptor-specific promoter to efficiently target the USH2D gene, whirlin, into both rod and cone photoreceptors. The transgenic whirlin was found to restore the changes of USH2A and GPR98 expression in the whirlin knockout retina (Zou et al., 2011). These encouraging progresses in the USH1B and USH2D mouse models lay a solid foundation for a further and

Aminoglycosides and their derivatives can induce a read-through of nonsense mutations by inserting an amino acid at the stop codon. These drugs have been tested in vitro, in cell cultures and in retinal explants to suppress the nonsense mutations found in USH1F (PCDH15) and USH1C (harmonin) patients (Rebibo-Sabbah et al., 2007; Nudelman et al., 2009; Goldmann et al., 2010; Nudelman et al., 2010). However, the high cellular toxicity of

detailed exploration of gene therapy for these and other USH subtypes.

demonstrated at the ankle links.

supplements (Yang et al., 2011).

photoreceptor loss in this animal model.

**7. Therapeutic studies** 

The research on USH has made tremendous progress since the discovery of its first causative gene, *MYO7A*, in 1995. Currently, nine genes have been identified responsible for this genetic disease. From the functional domain analysis, these genes have been proposed to participate in trafficking, scaffolding, cell adhesion, and signaling in cells. Many spontaneous and transgenic mouse, rat, and zebrafish models are available now. The majority of these animal models reproduce the hearing and balance problems in USH patients. However, not many of them manifest retinal degeneration, which is one of the typical symptoms in USH patients. The reason for this discrepancy is not clear. But lack of retinal phenotypes in these animal models hinders our studies on retinitis pigmentosa in USH patients. A large body of evidence from biochemical and cellular localization studies demonstrate that USH proteins are organized into multi-component complexes mainly in hair cells and photoreceptors. They play a role in hair bundle cohesion, mechanotransduction, and, possibly, protein/organelle transport in vivo. USH is an incurable disease. Effective treatments using different approaches are still being sought and explored.
