Gene therapy for hearing loss: challenges and the promise of cellular plasticity and epigenetic modulation

Abstract

Hearing loss can profoundly impact an individual's quality of life, affecting communication, social interactions, and overall well-being. Many people with hearing impairment report feelings of isolation, frustration, and decreased confidence in social settings, which can lead to withdrawal from activities they once enjoyed. Genetics plays a significant role in congenital hearing loss, accounting for approximately half of all cases. While gene therapy holds immense promise for restoring hearing function in cases of hereditary hearing loss (HHL), current methods face certain challenges that must be overcome to successfully develop therapeutic approaches. This review will explore these challenges and offer a perspective on how epigenetic modulation has the potential to address them, potentially revolutionizing the treatment of genetic hearing disorders.

Keywords: HDAC inhibitors; adeno-associated virus; epigenetics; gene therapy; hearing loss; partial reprogramming.

Figure 1

Schematic representation of the organ of Corti and its associated key structures in the inner ear. The central image depicts the overall structure of the organ of Corti. Surrounding this are detailed illustrations of key components: the hair bundle, hair cell (nucleus and cytoplasm), supporting cell, hair cell-auditory neuron synapses, and auditory neuron. The basilar membrane, tectorial membrane, and cell–cell junction are shown separately. Each component is annotated with genes associated with hearing loss. This figure highlights the complex genetic landscape underlying hereditary hearing loss and the diverse cellular structures involved in auditory function. This schematic representation provides a simplified overview of the major structural components without depicting precise anatomical proportions between inner and outer hair cells or their bundles. For clarity and focus on key genetic elements, specialized structures such as inner phalangeal cells, border cells, and the tonotopic organization of the tectorial membrane are not illustrated, though they play important roles in auditory function.

Figure 2

Expanding the critical window for gene therapy in sensorineural hearing loss. This figure illustrates how Yamanaka factors (OSKM) and/or epigenetic modifiers (such as, HDAC inhibitors) can potentially increase plasticity in mature cochlear cells after the critical window. This increased plasticity may allow gene therapy approaches to be effective even in later stages, potentially expanding the treatment opportunities for sensorineural hearing loss.