Ahmed, H., Shubina-Oleinik, O, Holt, J.R., Emerging Gene Therapies for Genetic Hearing Loss JARO 18(5): https://doi.org/10.1007/s10162-017-0634-8 https://link.springer.com/article/10.1007/s10162-017-0634-8
Many forms of human and animal hearing loss result from genetic causes related to the functioning of the cochlea, and these are typically defined as syndromic (genetic causes that influence the function of multiple organs) and nonsyndromic (causes that, as far as we know, only affect hearing). The nonsyndromic causes may be specifically amenable to specific manipulations of gene expression limited to the inner ear, and thus are potential targets for gene therapy. (Syndromic causes in theory should also be amenable to gene therapy, at least with respect to restoration of hearing function independent of restoration of function in other organs.) This review in JARO outlines in a comprehensive manner the challenges of delivery of viruses to the appropriate compartments of the inner ear and the limitations and advantages of different viral types, as well as approaches for non-viral delivery.
Additional considerations related to the target cell types are also discussed; not all viral packaging systems seem to work equally well in different cell types even within a single organ system. Indeed, although this is one of the challenges in gene delivery, it also presents opportunities for targeting specific types of cells within the cochlear and vestibular epithelia, without necessarily transducing the gene in all cells. This might be particularly important in certain types of channelopathies, for example, where the expression of specific channels is normally restricted to certain cell types, and where the ectopic expression of functioning channels in other cell types might be deleterious rather than helpful.
There have been some recent successes in using gene therapy to at least partially restore hearing in animal models with specific known genetic causes of hearing loss. It is important to note that most of these demonstrations have at best only restored hearing to a limited extent by lowering thresholds for objective detection of auditory responsiveness using the auditory brainstem response, distortion product otoacoustic emissions, or acoustic startle. There has been no demonstration of behavioral discrimination ability that would suggest that restoration of functions such as understanding conspecific vocalizations (or human speech), or discrimination of environmental sounds, might result from these therapies, although certainly that is the long-term hope. Restoration of such functions may depend on not only on achieving an acceptable level of peripheral sensitivity, but also on the appropriate engagement of central plasticity mechanisms (experience and training) so that the brain can make sense of, and optimally use, the new or restored inputs.
At the end of the review, the authors also consider the larger issues involved in translation of these approaches into the clinic. Given that there have been other successes in the preliminary application of gene therapies in clinical settings, there is a strong hope that eventually this approach may be effectively used for at least partial restoration of hearing and balance function.
This review raises many critical issues in the implementation of gene therapy approaches to hearing restoration. Although the approach certainly appears viable, there is a long way to go in understanding how to best implement the therapy for different genetic causes of hearing loss before it can be widely used in humans.
Ears and sound localization
Rik J. Otte, Martijn J. H. Agterberg, Marc M. Van Wanrooij, Ad F. M. Snik, A. John Van Opstal Age-related Hearing Loss and Ear Morphology Affect Vertical but not Horizontal Sound-Localization Performance JARO, 14(2): 261-273, 2013. doi: 10.1007/s10162-012-0367-7.
Sound localization involves the use of several different kinds of cues that are present in the sound arriving at the eardrum. The classical cues are the interaural time differences that occur because of different travel times for a sound from it’s source to the two ears, and interaural level differences that arise from the acoustic shadow of the head. Another rich set of cues arises from the structure of the external ear, or pinnae. These cues are largely found at high frequencies, and arise from reflections of the sound within the pinnae, which in turn shape the spectral structure of the sound reaching the ears. Pinnae cues are especially important for localizing sounds in elevation (as opposed to azimuth).
The pinna grows and changes shape as we age, and so the cues that are available are not constant over life. In a paper current in JARO On-line first, Ostal et al. tested the sound localization abilities of individuals at different ages using brief broadband sounds, for which spectral cues are important. Ear size was found to influence how well individuals at the different ages could localize sounds, and the larger ears of older adults enabled the use of lower frequency cues. However, the shift in the ability to use cues in different spectral ranges was not sufficient to offset the effects of age-related hearing loss, as older individuals were also poorer at the elevation localization task.
The paper raises an interesting set of questions regarding central processing. If the pinna is growing, then the relationship between the spectral structure and sound location in azimuth is always changing. The central auditory system clearly has to adapt to this shift, and I leave it as an exercise for the reader to provide hypotheses and mechanisms regarding where and how such adaptations occur. Access the full article at Springer.com.