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Deafness: from genetic architecture to gene therapy

Nature Reviews Genetics volume 24, pages 665–686 (2023)Cite this article

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Abstract

Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the elucidation of the molecular mechanisms underlying auditory system function, primarily in the cochlea, the mammalian hearing organ. These studies have provided unparalleled insights into the pathophysiological processes involved in SNHI, paving the way for the development of inner-ear gene therapy based on gene replacement, gene augmentation or gene editing. The application of these approaches in preclinical studies over the past decade has highlighted key translational opportunities and challenges for achieving effective, safe and sustained inner-ear gene therapy to prevent or cure monogenic forms of SNHI and associated balance disorders.

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Fig. 1: Schematic representation of the structure and functions of the inner ear.
Fig. 2: Inner-ear gene therapy methods.
Fig. 3: Routes for the delivery of inner-ear gene therapy.

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Acknowledgements

The authors thank P. Avan for fruitful discussions on physiological aspects and N. Michalski, S. Delmaghani and J. Boutet de Monvel for critical reading of the manuscript. The authors also thank C. Calvet (IdA) for help with the figures and E. Gomard for assistance with cochlea drawings (Communication Institutionnelle et Image, Institut Pasteur). This work was supported by Fondation pour l’Audition (FPA IDA05 to CP; FPA IDA08 to SS), Ile de France (DIM Thérapie génique to C.P. and S.S.), EARGENCURE (ANR-17-CE18–0027 to S.S.), PRESAGE (ANR-21-CE14–0075 to C.P.), RHU AUDINNOVE (ANR-18-RHUS-0007 to C.P. and S.S.).

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Authors and Affiliations

  1. Institut Pasteur, Université Paris Cité, Inserm, Institut de l’Audition, F-75012, Paris, France

    Christine Petit, Crystel Bonnet & Saaïd Safieddine

  2. Collège de France, F-75005, Paris, France

    Christine Petit

  3. Centre National de la Recherche Scientifique, F-75016, Paris, France

    Saaïd Safieddine

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C.P. and C.B. researched the literature. C.P. and S.S. wrote the article. All authors reviewed and/or edited the manuscript.

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Van Camp, G., Smith, R. J. H. Hereditary Hearing Loss Homepage: https://hereditaryhearingloss.org

Supplementary information

Glossary

Adeno-associated virus

(AAV). Single-stranded DNA virus from which recombinant AAVs are engineered as vectors for gene therapy for DNA delivery to target cells.

Antisense oligonucleotides

(ASOs). Short, synthetic, single-stranded sequences of 15–30 nucleotides designed to target other nucleotide sequences, usually coding or non-coding RNAs. They can mediate target RNA degradation, act as steric blockers and modulate exon splicing.

Canalostomy

A surgical approach to the inner ear involving fenestration of a vestibule semicircular canal, generally the posterior semicircular canal; used in inner-ear gene therapy interventions in mice.

Cochlear implant

A surgically implanted neuroprosthesis consisting of an electrical device that processes sounds and transforms acoustic stimulation into electrical stimulation delivered directly to the primary auditory neurons via electrodes inserted into the cochlea.

Conductive

Hearing impairment resulting from the defective transmission of sound waves to the cochlea due to external and/or middle-ear defects.

Dominant-negative variant

The product of a mutated gene carrying a variant with a dominant-negative effect has not only lost its function, but it also interferes in a deleterious manner with the function of the normal, wild-type gene product present within the same cell of heterozygous organisms.

Episome

A genetic determinant (such as the DNA of some bacteriophages) that can replicate autonomously in bacterial cytoplasm or as an integral part of the chromosomes.

Gene editing

Processes that change genomic DNA by adding, removing or altering sequences. Gene editing technologies produce site-specific modifications.

Gene replacement

A procedure for correcting the effects of defective genes by transferring a normal copy of the gene into targeted diseased cells.

Genetic architecture

The underlying genetic basis of the phenotypic features of a disease or other trait. It includes all the causal variants, the magnitude of their effects, their frequency and their interactions with each other and with environmental factors.

Genome-wide association studies

(GWAS). A genetic approach for identifying genetic risk factors for complex diseases or traits, by scanning for genome-wide associations between single-nucleotide polymorphisms (SNPs) and phenotypes.

Haploinsufficient gene

A gene that must have two normally functioning alleles for a normal phenotype.

Hearing aid

An auditory prosthesis; specifically, an electrical device amplifying sound at selected frequencies.

Hearing impairment

Used interchangeably with ‘deafness’ in this Review (deafness not being restricted to profound hearing impairment). Hearing impairment in humans is classified as mild, moderate, moderately severe, severe and profound, for threshold elevations ranging from 26–40 dB hearing level (HL), 41–55 dB HL, 56–70 dB HL, 71–90 dB HL and >90 dB HL, respectively, relative to normal human hearing thresholds.

Hearing threshold

The minimal intensity a sound of a given frequency must reach to be detected; measured in dB SPL (sound pressure level), with 0 dB SPL corresponding to 20 µPa. In clinical context, thresholds are obtained at four frequencies of 0.5, 1, 2 and 4 kHz and are expressed in dB on the Hearing Level (dB HL) scale. 0 dB HL represents for each frequency the average auditory threshold of individuals with normal hearing.

Heterochrony

Evolutionary change in timing and rates of developmental processes.

Homozygosity mapping

A method to identify genomic regions containing causal mutations for recessively inherited diseases through homozygous polymorphic markers co-inherited with the disease. Homozygous regions are generally large for recent consanguineous unions and shorter in cases of ancestral population homozygosity.

Meniere disease

A chronic inner-ear disorder characterized by episodes of vertigo (dizzy spells), tinnitus (perception of sound without an external sound stimulus) and hearing loss.

Ribbon pre-synapse

An electron-dense structure present in the sensory cells of various sensory systems, to which synaptic vesicles are tethered. In the mature auditory system, presynaptic ribbons are present only in inner hair cells. Each ribbon pre-synapse faces the post-synaptic ending of the single dendrite of the primary afferent neuron.

Small interfering RNA

Molecular effectors of RNA interference (RNAi). These double-stranded small RNAs, 19–25 bp long, can be used to inhibit transcription, degrade RNA and repress mRNA translation.

SNP

(Single-nucleotide-polymorphism). A single-base genomic variant. A variant is considered to be a SNP if its frequency exceeds 1% in a large population of unrelated individuals.

Stria vascularis

A highly specialized three-layered epithelium of the lateral wall of the cochlear duct housing a dense capillary network. The stria vascularis is involved in K+ secretion into the endolymph and the generation of endocochlear potential.

Tonotopic

Expression of gradients in the representation (maps) of sound properties, such as their frequency-to-place representation, or frequency maps of pure tone stimuli, from the cochlea to the primary auditory cortex and in all the nuclei of the auditory sensory pathway in between.

Usher syndrome

(USH). An autosomal recessively inherited multisensory disorder, with three clinical subtypes (USH1–3). The most severe subtype, USH1, combines congenital severe-to-profound sensorineural deafness, balance defects of vestibular origin and retinitis pigmentosa leading to blindness.

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Petit, C., Bonnet, C. & Safieddine, S. Deafness: from genetic architecture to gene therapy. Nat Rev Genet 24, 665–686 (2023). https://doi.org/10.1038/s41576-023-00597-7

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