-
Hearing Research Sep 2020Adeno-associated viruses (AAVs) are preferred vectors for gene replacement therapy, as they are non-pathogenic, non-inflammatory, induce stable transgene expression in... (Review)
Review
Adeno-associated viruses (AAVs) are preferred vectors for gene replacement therapy, as they are non-pathogenic, non-inflammatory, induce stable transgene expression in terminally differentiated cells, and a series of natural and engineered capsid proteins can be employed to target the vectors to specific cells. Only one feature of AAVs is limiting: the low cargo capacity for foreign DNA, restricting their application to coding sequences of <4 kb. In the last decade, splitting larger cDNAs into two AAVs and co-transducing tissue with such dual-AAV vectors has shown to result in the expression of the full-length protein in different tissues like retina, muscle and liver. This is due to the intrinsic capability of the AAV genomes to undergo homologous recombination and/or head-to-tail multimerization in nuclei of target cells. Recently, two groups independently found that a dual-AAV approach successfully delivered the 6 kb full-length otoferlin cDNA into inner hair cells of otoferlin knock-out mice and restored hearing. These pioneering studies pave the way for gene therapeutics that use dual-AAV vectors to restore hearing in forms of deafness caused by mutations in large genes.
Topics: Animals; Dependovirus; Ear, Inner; Genetic Therapy; Genetic Vectors; Membrane Proteins; Transgenes
PubMed: 31810595
DOI: 10.1016/j.heares.2019.107857 -
Journal of the Association For Research... Feb 2020This study aims to document the historical conceptualization of the inner ear as the anatomical location for the appreciation of sound at a continuum of frequencies and... (Review)
Review
This study aims to document the historical conceptualization of the inner ear as the anatomical location for the appreciation of sound at a continuum of frequencies and to examine the evolution of concepts of tonotopic organization to our current understanding. Primary sources used are from the sixth century BCE through the twentieth century CE. Each work/reference was analyzed from two points of view: to understand the conception of hearing and the role of the inner ear and to define the main evidential method. The dependence on theory alone in the ancient world led to inaccurate conceptualization of the mechanism of hearing. In the sixteenth century, Galileo described the physical and mathematical basis of resonance. The first theory of tonotopic organization, advanced in the seventeenth century, was that high-frequency sound is mediated at the apex of the cochlea and low-frequency at the base of the cochlea. In the eighteenth and nineteenth centuries, more accurate anatomical information was developed which led to what we now know is the accurate view of tonotopic organization: the high-frequency sound is mediated at the base and low-frequency sound at the apex. The electrical responses of the ear discovered in 1930 allowed for physiological studies that were consistent with the concept of a high to low tone sensitivity continuum from base to apex. In the mid-twentieth century, physical observations of models and anatomical specimens confirmed the findings of greater sensitivity to high tones at the base and low tones at the apex and, further, demonstrated that for high-intensity sound, there was a spread of effect through the entire cochlea, more so for low-frequency tones than for high tones. Animal and human behavioral studies provided empirical proof that sound is mediated at a continuum of frequencies from high tones at the base through low tones at the apex of the cochlea. Current understanding of the tonotopic organization of the inner ear with regard to pure tones is the result of the acquisition over time of knowledge of acoustics and the anatomy, physical properties, and physiology of the inner ear, with the ultimate verification being behavioral studies. Examination of this complex evolution leads to understanding of the way each approach and evidential method through time draws upon previously developed knowledge, with behavioral studies providing empirical verification.
Topics: Anatomy; Animals; Ear, Inner; Hearing; History, 16th Century; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, Ancient; Humans; Physiology
PubMed: 32020418
DOI: 10.1007/s10162-019-00741-3 -
International Journal of Molecular... Dec 2020This review provides an up-to-date source of information on the primary auditory neurons or spiral ganglion neurons in the cochlea. These neurons transmit auditory... (Review)
Review
This review provides an up-to-date source of information on the primary auditory neurons or spiral ganglion neurons in the cochlea. These neurons transmit auditory information in the form of electric signals from sensory hair cells to the first auditory nuclei of the brain stem, the cochlear nuclei. Congenital and acquired neurosensory hearing loss affects millions of people worldwide. An increasing body of evidence suggest that the primary auditory neurons degenerate due to noise exposure and aging more readily than sensory cells, and thus, auditory neurons are a primary target for regenerative therapy. A better understanding of the development and function of these neurons is the ultimate goal for long-term maintenance, regeneration, and stem cell replacement therapy. In this review, we provide an overview of the key molecular factors responsible for the function and neurogenesis of the primary auditory neurons, as well as a brief introduction to stem cell research focused on the replacement and generation of auditory neurons.
Topics: Animals; Base Sequence; Brain Stem; Cochlea; Cochlear Nucleus; Ear, Inner; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Induced Pluripotent Stem Cells; Mice; Mutation; Neurogenesis; Neurons; Regenerative Medicine; Spiral Ganglion
PubMed: 33374462
DOI: 10.3390/ijms22010131 -
Viruses Jan 2021Hearing loss, one of the most prevalent chronic health conditions, affects around half a billion people worldwide, including 34 million children. The World Health... (Review)
Review
Hearing loss, one of the most prevalent chronic health conditions, affects around half a billion people worldwide, including 34 million children. The World Health Organization estimates that the prevalence of disabling hearing loss will increase to over 900 million people by 2050. Many cases of congenital hearing loss are triggered by viral infections during different stages of pregnancy. However, the molecular mechanisms by which viruses induce hearing loss are not sufficiently explored, especially cases that are of embryonic origins. The present review first describes the cellular and molecular characteristics of the auditory system development at early stages of embryogenesis. These developmental hallmarks, which initiate upon axial specification of the otic placode as the primary root of the inner ear morphogenesis, involve the stage-specific regulation of several molecules and pathways, such as retinoic acid signaling, Sonic hedgehog, and Wnt. Different RNA and DNA viruses contributing to congenital and acquired hearing loss are then discussed in terms of their potential effects on the expression of molecules that control the formation of the auditory and vestibular compartments following otic vesicle differentiation. Among these viruses, cytomegalovirus and herpes simplex virus appear to have the most effect upon initial molecular determinants of inner ear development. Moreover, of the molecules governing the inner ear development at initial stages, SOX2, FGFR3, and CDKN1B are more affected by viruses causing either congenital or acquired hearing loss. Abnormalities in the function or expression of these molecules influence processes like cochlear development and production of inner ear hair and supporting cells. Nevertheless, because most of such virus-host interactions were studied in unrelated tissues, further validations are needed to confirm whether these viruses can mediate the same effects in physiologically relevant models simulating otic vesicle specification and growth.
Topics: Animals; Cell Differentiation; Cyclin-Dependent Kinase Inhibitor p27; Cytomegalovirus; Ear, Inner; Hearing Loss; Humans; Receptor, Fibroblast Growth Factor, Type 3; SOXB1 Transcription Factors; Signal Transduction; Simplexvirus
PubMed: 33419104
DOI: 10.3390/v13010071 -
Hearing Research Dec 2022Various animal models have been established and applied in hearing research. In the exploration of novel cochlear implant developments, mainly rodents have been used....
OBJECTIVES
Various animal models have been established and applied in hearing research. In the exploration of novel cochlear implant developments, mainly rodents have been used. Despite their important contribution to the understanding of auditory function, translation of experimental observations from rodents to humans is limited due to the size differences and genetic variability. Large animal models with better representation of the human cochlea are sparse. For this reason, we evaluated domestic piglets and Aachen minipigs for the suitability as a cochlear implantation animal model with commercially available cochlear implants.
METHODS
Four domestic piglets (two male and two female) and six Aachen minipigs were implanted with either MED-EL Flex24 or Flex20 cochlear implants respectively, after a step-by-step surgical approach was trained with pig cadavers. Electrophysiological measurements were performed before, during and after implantation for as long as 56 days after surgery. Auditory brainstem responses, electrocochleography as well as electrically and acoustically evoked compound action potentials were recorded. Selected cochleae were further analyzed histologically or with micro-CT imaging.
RESULTS
A surgical approach was established using a retroauricular single incision. Baseline auditory thresholds were 27 ± 3 dB sound pressure level (SPL; auditory brainstem click responses, mean ± standard error of the mean) and ranged between 30 and 80 dB SPL in frequency-specific responses (0.5 - 32 kHz). Follow-up measurements revealed deafness within the first two weeks after surgery, but some animals partially recovered to a hearing threshold of 80 dB SPL in certain frequencies as well as in click responses. Electrically evoked compound action potential thresholds increased within the first week after surgery, which led to lower stimulation responses or increase of necessary charge input. Immune reactions and consecutive scalar fibrosis following implantation were confirmed with histological analysis of implanted cochleae and may result in increased impedances. A three-dimensional minipig micro-CT segmentation revealed cochlear volumetric data similar to human inner ear dimensions.
CONCLUSIONS
This study underlines the feasibility of cochlear implantation with clinically used cochlear implants in a large animal model with representative inner ear dimensions comparable to humans. To bridge the gap between small animal models and humans in translational research and to account for the structural and size differences, we recommend the minipig as a valuable animal model for hearing research. First insights into the induced trauma in minipigs after cochlear implant surgery and a partial hearing recovery present important data of the cochlear health changes in large animal cochleae.
Topics: Animals; Male; Female; Humans; Swine; Cochlear Implantation; Swine, Miniature; Cochlear Implants; Cochlea; Evoked Potentials, Auditory, Brain Stem; Auditory Threshold; Hearing
PubMed: 36343533
DOI: 10.1016/j.heares.2022.108644 -
In Vivo (Athens, Greece) 2021Hearing loss is one of the major worldwide health problems that seriously affects human social and cognitive development. In the auditory system, three components outer... (Review)
Review
Hearing loss is one of the major worldwide health problems that seriously affects human social and cognitive development. In the auditory system, three components outer ear, middle ear and inner ear are essential for the hearing mechanism. In the inner ear, sensory hair cells and ganglion neuronal cells are the essential supporters for hearing mechanism. Damage to these cells can be caused by long-term exposure of excessive noise, ototoxic drugs (aminoglycosides), ear tumors, infections, heredity and aging. Since mammalian cochlear hair cells do not regenerate naturally, some therapeutic interventions may be required to replace the damaged or lost cells. Cochlear implants and hearing aids are the temporary solutions for people suffering from severe hearing loss. The current discoveries in gene therapy may provide a deeper understanding in essential genes for the inner ear regeneration. Stem cell migration, survival and differentiation to supporting cells, cochlear hair cells and spiral ganglion neurons are the important foundation in understanding stem cell therapy. Moreover, mesenchymal stem cells (MSCs) from different sources (bone marrow, umbilical cord, adipose tissue and placenta) could be used in inner ear therapy. Transplanted MSCs in the inner ear can recruit homing factors at the damaged sites to induce transdifferentiation into inner hair cells and ganglion neurons or regeneration of sensory hair cells, thus enhancing the cochlear function. This review summarizes the potential application of mesenchymal stem cells in hearing restoration and combining stem cell and molecular therapeutic strategies can also be used in the recovery of cochlear function.
Topics: Animals; Ear, Inner; Hair Cells, Auditory, Inner; Humans; Mesenchymal Stem Cells; Spiral Ganglion; Stem Cell Transplantation
PubMed: 33402445
DOI: 10.21873/invivo.12227 -
LDL receptor-related protein 1 (LRP1), a novel target for opening the blood-labyrinth barrier (BLB).Signal Transduction and Targeted Therapy Jun 2022Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier...
Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.
Topics: Drug Delivery Systems; Ear, Inner; Hearing Loss; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Pharmaceutical Preparations
PubMed: 35680846
DOI: 10.1038/s41392-022-00995-z -
Stem Cell Reports Jun 2020Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant... (Review)
Review
Sensorineural hearing loss and vestibular dysfunction are caused by damage to neurons and mechanosensitive hair cells, which do not regenerate to any clinically relevant extent in humans. Several protocols have been devised to direct pluripotent stem cells (PSCs) into inner ear hair cells and neurons, which display many properties of their native counterparts. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development. Modeling human diseases in vitro through genetic manipulation of PSCs is already feasible, thereby permitting the elucidation of mechanistic understandings of a wide array of disease etiologies. Early studies on transplantation of PSC-derived otic progenitors have been successful in certain animal models, yet restoration of function and long-term cell survival remain unrealized. Through further research, PSC-based approaches will continue to revolutionize our understanding of inner ear biology and contribute to the development of therapeutic treatments for inner ear disorders.
Topics: Animals; Ear, Inner; Hearing Loss, Sensorineural; Humans; Neural Stem Cells; Neurogenesis; Pluripotent Stem Cells; Stem Cell Transplantation
PubMed: 32442531
DOI: 10.1016/j.stemcr.2020.04.008 -
Hearing Research Sep 2022Cochlear distortions afford researchers and clinicians a glimpse into the conditions and properties of inner ear signal processing mechanisms. Until recently, our... (Review)
Review
Cochlear distortions afford researchers and clinicians a glimpse into the conditions and properties of inner ear signal processing mechanisms. Until recently, our examination of these distortions has been limited to measuring the vibration of the basilar membrane or recording acoustic distortion output in the ear canal. Despite its importance, the generation mechanism of cochlear distortion remains a substantial task to understand. The ability to measure the vibration of the reticular lamina in rodent models is a recent experimental advance. Surprising mechanical properties have been revealed. These properties merit both discussion in context with our current understanding of distortion, and appraisal of the significance of new interpretations of cochlear mechanics. This review focusses on some of the recent data from our research groups and discusses the implications of these data on our understanding of vocalization processing in the periphery, and their influence upon future experimental directions. This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam.
Topics: Acoustic Stimulation; Basement Membrane; Basilar Membrane; Cochlea; Hair Cells, Auditory, Outer; Vibration
PubMed: 34916081
DOI: 10.1016/j.heares.2021.108405 -
Cell Reports Sep 2022The avian utricle, a vestibular organ of the inner ear, displays turnover of sensory hair cells throughout life. This is in sharp contrast to the mammalian utricle,...
The avian utricle, a vestibular organ of the inner ear, displays turnover of sensory hair cells throughout life. This is in sharp contrast to the mammalian utricle, which shows limited regenerative capacity. Here, we use single-cell RNA sequencing to identify distinct marker genes for the different sensory hair cell subtypes of the chicken utricle, which we validated in situ. We provide markers for spatially distinct supporting cell populations and identify two transitional cell populations of dedifferentiating supporting cells and developing hair cells. Trajectory reconstruction resulted in an inventory of gene expression dynamics of natural hair cell generation in the avian utricle.
Topics: Animals; Chickens; Epithelial Cells; Hair Cells, Auditory; Mammals; Saccule and Utricle
PubMed: 36170825
DOI: 10.1016/j.celrep.2022.111432