Abstract
Abstract The process of hearing involves a series of events. The energy of sound is captured by the outer ear and further transferred through the external auditory canal to the middle ear. In the middle ear, sound waves are converted into movements of the tympanic membrane and the ossicles, thereby amplifying the pressure so that it is sufficient to cause movement of the cochlear fluid. The traveling wave within the cochlea leads to depolarization of the inner ear hair cells that, in turn, release the neurotransmitter glutamate. Thereby, the spiral ganglion neurons are activated to transfer the signals via the auditory pathway to the primary auditory cortex. This complex combination of mechanosensory and physiological mechanisms involves many distinct types of cells, the function of which are impacted by numerous proteins, including those involved in ion channel activity, signal transduction and transcription. In the last 30 years, pathogenic variants in over 150 genes were found to be linked to hearing loss. Hearing loss affects over 460 million people world-wide, and current treatment approaches, such as hearing aids and cochlear implants, serve to improve hearing capacity but do not address the underlying genetic cause of hearing loss. Therefore, therapeutic strategies designed to correct the genetic defects causative for hearing loss offer the possibility to treat these patients. In this review, we will discuss genetic causes of hearing loss, novel gene therapeutic strategies to correct hearing loss due to gene defects and some of the preclinical studies in hearing loss animal models as well as the clinical translation of gene therapy approaches to treat hearing loss patients.
Highlights
Genetic diagnosis of hearing loss allows prognostic disease assessment and provides the opportunity for early therapeutic intervention
This complex combination of mechanosensory and physiological mechanisms involves many distinct types of cells, the function of which are impacted by numerous proteins, including those involved in ion channel activity, signal transduction and transcription
In combination with the extensive information acquired from animal models, gene transfer and genomic modification technologies are expected to drive clinical development of novel gene therapy strategies to treat hearing loss patients
Summary
Genetic diagnosis of hearing loss allows prognostic disease assessment and provides the opportunity for early therapeutic intervention. Identification of genes associated with hearing loss has led to deeper insight into the underlying biology of normal hearing and pathology of hearing loss. Coupled with our increased understanding of genetics and advances in molecular biology techniques, this information has greatly facilitated design of novel medical strategies to treat hereditary hearing loss, such as gene therapy approaches. The first clinical trial testing gene therapy in hearing loss patients was initiated and there are several gene transfer modalities available for further evaluation and optimization
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