Emerging Gene Therapies for Genetic Hearing Loss

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Abstract

<p class="first" id="Par1">Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of-principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic. </p>

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Efficient Delivery of Genome-Editing Proteins In Vitro and In Vivo

John Zuris, David Thompson, Yilai Shu … (2014)

Efficient intracellular delivery of proteins is needed to fully realize the potential of protein therapeutics. Current methods of protein delivery commonly suffer from low tolerance for serum, poor endosomal escape, and limited in vivo efficacy. Here we report that common cationic lipid nucleic acid transfection reagents can potently deliver proteins that are fused to negatively supercharged proteins, that contain natural anionic domains, or that natively bind to anionic nucleic acids. This approach mediates the potent delivery of nM concentrations of Cre recombinase, TALE- and Cas9-based transcriptional activators, and Cas9:sgRNA nuclease complexes into cultured human cells in media containing 10% serum. Delivery of Cas9:sgRNA complexes resulted in up to 80% genome modification with substantially higher specificity compared to DNA transfection. This approach also mediated efficient delivery of Cre recombinase and Cas9:sgRNA complexes into the mouse inner ear in vivo, achieving 90% Cre-mediated recombination and 20% Cas9-mediated genome modification in hair cells.

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Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

D P Kelsell, J Dunlop, H P Stevens … (1997)

Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

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Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms.

M. Liberman, Sharon G Kujawa (2017)

Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional 'hearing loss' arising from several common causes in humans.