Gene Therapy for Human Sensorineural Hearing Loss

Abstract

Hearing loss is the most common sensory impairment in humans and currently disables 466 million people across the world. Congenital deafness affects at least 1 in 500 newborns, and over 50% are hereditary in nature. To date, existing pharmacologic therapies for genetic and acquired etiologies of deafness are severely limited. With the advent of modern sequencing technologies, there is a vast compendium of growing genetic alterations that underlie human hearing loss, which can be targeted by therapeutics such as gene therapy. Recently, there has been tremendous progress in the development of gene therapy vectors to treat sensorineural hearing loss (SNHL) in animal models in vivo. Nevertheless, significant hurdles remain before such technologies can be translated toward clinical use. These include addressing the blood-labyrinth barrier, engineering more specific and effective delivery vehicles, improving surgical access, and validating novel targets. In this review, we both highlight recent progress and outline challenges associated with in vivo gene therapy for human SNHL.

Keywords: Anc80L65; adeno-associated virus (AAV); blood labyrinth barrier; gene therapy; nanoparticles; round window niche; tumor penetrating peptide.

Figure 1

Schematic illustrating methods of delivering therapeutics to the human ear. (A) The relevant structures through which drugs such as gene therapy agents, nanoparticles, or biologics are introduced into the inner ear are labeled in red, and include both indirect and direct approaches. The indirect approach is through the tympanic membrane (transtympanic or intratympanic) to deposit the therapeutic in the middle ear and allow it to diffuse into the inner ear via the oval and round windows. Direct approaches include delivery into the cochlea through application over or through the round window membrane, through a surgically drilled cochleostomy adjacent to the round window, a fenestra in the bony oval window, or a semicircular canal. Approaches for drug/gene delivery also include combining existing technologies such as cochlear implant electrodes or stapes prosthesis during stapedotomy. (B) Endoscopic view of the anatomy of the human middle ear. The round window niche consists of bony overhang, and the round window is often obscured by a pseudomembrane. M, malleus manubrium; I, incus; P, cochlear promontory; S, stapes; FN, facial nerve; TM, tympanic membrane. Image reproduced with permission from Medscape Drugs & Diseases (https://emedicine.medscape.com/), Surgical Treatment of Meniere Disease, 2018, available at: https://emedicine.medscape.com/article/856658-overview.