The broader implications of this precise level of gene regulation are that concerns about tissue or cell type-specific targeting may be more easily overcome than previously learn more suspected. A key concern associated with viral-mediated gene transfer

is gene dosage, because the amount of gene product produced and the extent to which the cell can regulate it may vary widely. Results by Akil et al. (2012) suggest that the levels of VGLUT3 produced by the AAV were compatible with phenotypic rescue, providing hope that adequate levels of protein synthesis may be achieved in humans by this method. However, gene products relevant for other gene mutations may be more sensitive to gene dosage, such that gene replacement therapy Lumacaftor in vitro strategies will need to be developed specifically for each mutation. Despite the excitement raised by this study, several milestones will need to be reached before this approach can be used in humans. First,

proof that this method works in mature ears needs to be provided. Akil et al. (2012) used mouse pups that were 1–3 or 10–12 days old, both ages in which the mouse auditory system is still immature. The researchers determined that the phenotypic rescue worked better in the younger mice, which may suggest that the current method is less effective in truly mature tissues (∼P21 and later for the mouse cochlea). The decreased efficacy in older animals could reflect the maturity of hair cells or surrounding cells and tissues (leading to reduced plasticity), development of immune memory, or as-yet-undefined changes in the inner ear. Second, for applicability to human therapies, it may be necessary to correct most if not all aspects of the relevant underlying pathologies causing the deafness. For example, Akil et al. (2012) observed ongoing loss of spiral ganglion neurons, despite functional and structural improvements in the treated hair cells. Ongoing neuronal degeneration would probably degrade long-term

correction of inner ear defects and would need to be addressed for optimal treatment of patients with VGLUT3 mutations. Despite these limitations, the possibilities raised by this study warrant Electron transport chain high enthusiasm. For individuals with hereditary hearing loss who are currently treated with cochlear implants, there is reason to believe that approaches like this could lead to the development of significantly better, more specifically targeted therapies to correct their hearing. Gene therapy-based approaches will probably become relevant to genetic forms of hearing loss in which the underlying cells or proteins can be identified, especially in cases in which critical cells and tissues survive until the age at which gene transfer protocols can be used.