Gene therapy for deafness

Abstract

Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death, have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance the endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable.

Figure 1. Successful gene therapy must target a range of cell types in the cochlea

The diagram indicates a subset of the multiple differentiated cell types present in the cochlea and the endogenous or transgenic expression pattern of several genes that are required for auditory function. Inner hair cells (IHC) and outer hair cells (OHC) are the mechanosensory cells in the cochlea and connect to fibers of spiral ganglion cells (SG) of the auditory nerve. Multiple types of epithelial supporting cells (SC) provide mechanical and metabolic support to the hair cells. Cells of the stria vascularis (SV) are responsible for the high resting potential of endolymph that fills the central fluid-filled space (scala media) of the cochlea. Mutations in genes such as SLC26A4, which encodes the transmembrane Cl- and HCO₃- exchanger pendrin, and GJB2, which encodes the gap junction protein connexin 26, underlie common forms of genetic hearing loss . SLC26A4/pendrin is expressed in epithelial cells in the spiral prominence (SP), in root cells, and in spindle cells in the stria vascularis in light blue; ^, . GJB2 is expressed in supporting cells, in fibrocytes of the lateral wall and epithelial cells at the medial side of the cochlea (in gray), and in a subset of cells of the stria vascularis.^–. VGLUT3 (also known as SLC17A8), which encodes a vesicular glutamate transporter, is expressed in inner hair cells . Cochlear delivery of a wild type version of VGLUT3 rescued auditory function in mice homozygous for mutations in this gene (see text for details). Injection into the fluid-filled spaces of the cochlea of adenoviral or AAV vectors encoding BDNF resulted in expression of the neurotrophin in supporting cells and in mesothelial cells (MC; in dark blue) that line the scala tympani space and induced regrowth of auditory nerve fibers.^,