Gene Therapy for Sensorineural Hearing Loss

Abstract

Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss.

Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction

“…AAV is one of the most frequently used viral vectors in gene therapy, because it can efficiently infect a variety of post-mitotic tissues and result in stable gene expression, with minimal vector-related immune response and toxicity22023. Due to these advantages, AAV vectors have been safely used in the clinical studies over the past decades, which more recently led to demonstrable efficacy for monogenic disease approaches targeting muscle and retina353637.…”

“…In recent years, the use of viral vectors for gene therapy in the inner ear has received increasing attention as a way to treat either acquired or hereditary sensorineural hearing loss (for review see refs 1, 2, 3, 4, 5). The sensory epithelia of the inner ear are promising sites for viral therapies because they are isolated, in part, by a blood-labyrinth barrier, and because they are bathed in a continuous series of fluid-filled spaces encased in bone.…”

Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome

“…While attention has been given to cochlear gene therapy, few studies have assessed the efficacy of gene therapy in the inner ear vestibular system. [26][27][28][29] To our knowledge, the current study is the first to examine the effects of gene replacement therapy in a mouse model of hereditary balance and hearing dysfunction. Injection of AAV8-whirlin into the posterior semicircular canal successfully infected numerous hair cells throughout the vestibular system.…”

Genetics of Hearing Loss

“…Defining the genes and pathways responsible for normal hearing are paving the way towards developing new treatments for hearing impairments. Among the different approaches for newly developed hearing impairment treatments are the regeneration of inner ear sensory cells 101, 102 and the use of viral vectors for gene therapy 103 . These potential treatments will be helpful for both genetically and environmentally-related HL 11 .…”