Therapy For Sensorineural Hearing Loss Research Articles

Role of Oxidative Stress in Sensorineural Hearing Loss.

Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia-reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss.

Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from a multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis of auditory development and the growing compendium of deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered a relatively secure vector for gene therapy in clinical trials, can deliver various transgenes based on gene therapy strategies such as gene replacement, gene silencing, gene editing, or gene addition to alleviate diverse types of SNHL. This review delved into the preclinical advances in AAV-based gene therapy for SNHL, spanning hereditary and acquired types. Particular focus is placed on the dual-AAV construction method and its application, the vector delivery route of mouse inner ear models (local, systemic, fetal, and cerebrospinal fluid administration), and the significant considerations in transforming from AAV-based animal model inner ear gene therapy to clinical implementation.

Recent Advances and Future Research Directions for Hearing Loss Treatment Based on Nanoparticles

Sensorineural hearing loss is a prevailing health issue worldwide which usually occurs due to sensory inner ear cell destruction. These cells, once damaged, do not regenerate in mammals resulting in permanent hearing loss. Effective treatment of inner ear diseases is strongly correlated with efficient drug delivery to the inner ear. Researchers have made important efforts to deliver drugs locally to the inner ear in a safe and controllable manner. Different strategies and drug delivery systems were used to mitigate the resistance exerted by the multiple anatomical barriers found in the inner ear. Nanoparticles represent an option for sustained drug delivery to the inner ear. Nanocarrier-based systems can diffuse through the round and oval window membrane allowing for direct delivery into the inner ear components. Certain types of enhanced nanoparticles can focus on specific parts of the inner ear, providing targeted delivery which might represent the future therapy for sensorineural hearing loss. In this article, we will present the latest advances in the treatment of hearing loss based on nanoparticles.

Precision Medicine Shows Promise to Advance the Care of Individuals with Hearing Loss

Hearing loss (HL) is the most common sensory disorder worldwide and arises from a heterogeneous set of genetic and environmental etiologies. Currently, therapy for sensorineural HL is non-specific and limited to amplification devices and implanted neuroprosthetics. Recent advances in the burgeoning field of precision medicine focused on individualizing disease diagnosis and tailoring treatment to each patient’s own biology hold great promise to provide tailored care for hearing loss patients. In this review, we discuss the current diagnostic algorithm and treatment options for hearing loss, the advances in using precision medicine tools to identify specific genetic variants that predispose to or result in hearing loss, the role of genetics in determining surgical outcomes following cochlear implantation, recent advances in gene and stem cell therapies for treating hearing loss, and patient-specific disease modeling using induced pluripotent stem cells. All of these precision medicine techniques will result in improved care for patients based on the precise etiology of their hearing loss.

Regenerative Therapy for Sensorineural Hearing Loss: Recent Progress and Future Directions

Sensorineural Hearing Loss (SNHL) continues to be a significant public health problem with over 270 million affected people worldwide and an incidence that increases with age [1,2]. Some cases of SNHL have a genetic cause, but the majority of SHNL is the result of ototoxic insult [3]

Two Photon Fluorescence Microscopy of the Unstained Human Cochlea Reveals Organ of Corti Cytoarchitecture.

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide, and it typically originates from the cochlea. Methods to visualize intracochlear cells in living people are currently lacking, limiting not only diagnostics but also therapies for SNHL. Two-photon fluorescence microscopy (TPFM) is a high-resolution optical imaging technique. Here we demonstrate that TPFM enables visualization of sensory cells and auditory nerve fibers in an unstained, non-decalcified adult human cochlea.

A deep learning approach to quantify auditory hair cells

Hearing loss affects millions of people worldwide. Yet, there are still no curative therapies for sensorineural hearing loss. Frequent causes of sensorineural hearing loss are due to damage or loss of the sensory hair cells, the spiral ganglion neurons, or the synapses between them. Culturing the organ of Corti allows the study of all these structures in an experimental model, which is easy to manipulate. Therefore, the in vitro culture of the neonatal mammalian organ of Corti remains a frequently used experimental system, in which hair cell survival is routinely assessed. However, the analysis of the surviving hair cells is commonly performed via manual counting, which is a time-consuming process and the inter-rater reliability can be an issue.Here, we describe a deep learning approach to quantify hair cell survival in the murine organ of Corti explants. We used StarDist, a publicly available platform and plugin for Fiji (Fiji is just ImageJ), to train and apply our own custom deep learning model. We successfully validated our model in untreated, cisplatin, and gentamicin treated organ of Corti explants. Therefore, deep learning is a valuable approach for quantifying hair cell survival in organ of Corti explants. Moreover, we also demonstrate how the publicly available Fiji plugin StarDist can be efficiently used for this purpose.

A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss.

The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two‐dimensional and three‐dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based‐cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies.

Research advances on umbilical cord blood derived mesenchymal stem cell in therapy of sensorineural hearing loss

Sensorineural hearing loss（SNHL） is a difficult and hot issue in the field of otology. The effect of medications targeting the mechanism of SNHL are often unsatisfactory for hearing improvement. Hearing aids and cochlear implants are the mainstream treatment methods at present, but neither of them can reverse the pathological changes of affected inner ear. In recent years, mesenchymal stem cells transplantation has been confirmed by several animal studies and clinical trials to have great potential for clinical applications in restoring the structure of the inner ear and hearing improvement to some extent. In this review, we review the characteristics of umbilical cord blood derived mesenchymal stem cells（UCBMSCs）, the approaches of transplantation, the efficacy and mechanism of UCBMSCs in the treatment of SNHL, and the safety of clinical application, covering the existing problems and future prospects of this rising treatment.

Efficient In Utero Gene Transfer to the Mammalian Inner Ears by the Synthetic Adeno-Associated Viral Vector Anc80L65

Sensorineural hearing loss is one of the most common sensory disorders worldwide. Recent advances in vector design have paved the way for investigations into the use of adeno-associated vectors (AAVs) for hearing disorder gene therapy. Numerous AAV serotypes have been discovered to be applicable to inner ears, constituting a key advance for gene therapy for sensorineural hearing loss, where transduction efficiency of AAV in inner ear cells is critical for success. One such viral vector, AAV2/Anc80L65, has been shown to yield high expression in the inner ears of mice treated as neonates or adults. Here, to evaluate the feasibility of prenatal gene therapy for deafness, we assessed the transduction efficiency of AAV2/Anc80L65-eGFP (enhanced green fluorescent protein) after microinjection into otocysts in utero. This embryonic delivery method achieved high transduction efficiency in both inner and outer hair cells of the cochlea. Additionally, the transduction efficiency was high in the hair cells of the vestibules and semicircular canals and in spiral ganglion neurons. Our results support the potential of Anc80L65 as a gene therapy vehicle for prenatal inner ear disorders.

Genetic testing and genetic therapy for sensorineural hearing loss

Genetic testing and genetic therapy for sensorineural hearing loss

Avocado Oil Extract Modulates Auditory Hair Cell Function through the Regulation of Amino Acid Biosynthesis Genes.

Sensorineural hearing loss (SNHL) is one of the most common causes of disability, affecting over 466 million people worldwide. However, prevention or therapy of SNHL has not been widely studied. Avocado oil has shown many health benefits but it has not yet been studied in regards to SNHL. Therefore, we aimed to investigate the efficacy of avocado oil on SNHL in vitro and in vivo and elucidate its mode of action. For the present study, we used enhanced functional avocado oil extract (DKB122). DKB122 led to recovery of otic hair cells in zebrafish after neomycin-induced otic cell damage. Also, DKB122 improved auditory sensory transmission function in a mouse model of noise induced-hearing loss and protected sensory hair cells in the cochlea. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that DKB122 protected House Ear Institute-Organ of Corti 1 (HEI-OC1) cells against neomycin-related alterations in gene expression due to oxidative stress, cytokine production and protein synthesis.

Photobiomodulation promotes adenoviral gene transduction in auditory cells

Gene therapy is the delivery of a therapeutic gene into target cells to treat disorders by replacing disease-causing mutated genes with healthy ones. Gene therapy of the inner ear has been recently described, with applications for sensorineural hearing loss. However, gene delivery to the location of the inner ear, and thus efficacy of therapy, is challenging. Photobiomodulation (PBM) with a low-level laser has been suggested to have a therapeutic effect and has the potential to augment gene therapy. To investigate whether PBM improves the rate of adenovirus (Ad)-mediated viral delivery, we compared low-level laser therapy (LLLT) and non-LLLT HEI-OC1 cells treated with an Ad viral vector carrying green fluorescent protein (GFP). Cultured HEI-OC1 cells were divided into six groups: no treatment control, LLLT only, 1μL Ad-GFP, 3μL Ad-GFP, 1μL Ad-GFP + LLLT, and 3μL Ad-GFP + LLLT (LLLT: 808nm at 15mW for 15min). Cells were irradiated twice: at 2h and again at 24h. A nonparametric Mann-Whitney U test was used to statistically analyze differences between the control and treatment groups. The viral inoculations used in this study did not change the amount of viable HEI-OC1 cells (N = 4-8). The 1μL Ad-GFP + LLLT and 3μL Ad-GFP + LLLT groups showed an increased density of GFP-positive cells compared to 1μL and 3μL Ad-GFP cells (N = 5-8, 1μL: p = 0.0159; 3μL: p = 0.0168,). The quantitative analysis of the epifluorescence of the 1μL Ad-GFP + LLLT, and 3μL Ad-GFP + LLLT groups revealed increased GFP expression/cell compared to 1μL and 3μL Ad-GFP cells (N = 6-15, 1μL: p = 0.0082; 3μL: p = 0.0012). The RT-qPCR results were consistent (N = 4-5, p = 0.0159). These findings suggest that PBM may enhance the gene delivery of Ad-mediated viral transduction, and the combination of the two may be a promising tool for gene therapy for sensorineural hearing loss.

Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success.

Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included.

Emerging Therapies for Sensorineural Hearing Loss.

To critically review and evaluate the proposed mechanisms and documented results of the therapeutics currently in active clinical drug trials for the treatment of sensorineural hearing loss. US National Institutes of Health (NIH) Clinical Trials registry, MEDLINE/PubMed. A review of the NIH Clinical Trials registry identified candidate hearing loss therapies, and supporting publications were acquired from MEDLINE/PubMed. Proof-of-concept, therapeutic mechanisms, and clinical outcomes were critically appraised. Twenty-two active clinical drug trials registered in the United States were identified, and six potentially therapeutic molecules were reviewed. Of the six molecules reviewed, four comprised mechanisms pertaining to mitigating oxidative stress pathways that presumably lead to inner ear cell death. One remaining therapy sought to manipulate the cell death cascade, and the last remaining therapy was a novel cell replacement therapy approach to introduce a transcription factor that promotes hair cell regeneration. A common theme in recent clinical trials registered in the United States appears to be the targeting of cell death pathways and influence of oxidant stressors on cochlear sensory neuroepithelium. In addition, a virus-delivered cell replacement therapy would be the first of its kind should it prove safe and efficacious. Significant challenges for bringing these bench-to-bedside therapies to market remain. It is never assured that results in non-human animal models translate to effective therapies in the setting of human biology. Moreover, as additional processes are described in association with hearing loss, such as an immune response and loss of synaptic contacts, additional pathways for targeting become available.

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons.

The ability to generate spiral ganglion neurons (SGNs) from stem cells is a necessary prerequisite for development of cell‐replacement therapies for sensorineural hearing loss. We present a protocol that directs human embryonic stem cells (hESCs) toward a purified population of otic neuronal progenitors (ONPs) and SGN‐like cells. Between 82% and 95% of these cells express SGN molecular markers, they preferentially extend neurites to the cochlear nucleus rather than nonauditory nuclei, and they generate action potentials. The protocol follows an in vitro stepwise recapitulation of developmental events inherent to normal differentiation of hESCs into SGNs, resulting in efficient sequential generation of nonneuronal ectoderm, preplacodal ectoderm, early prosensory ONPs, late ONPs, and cells with cellular and molecular characteristics of human SGNs. We thus describe the sequential signaling pathways that generate the early and later lineage species in the human SGN lineage, thereby better describing key developmental processes. The results indicate that our protocol generates cells that closely replicate the phenotypic characteristics of human SGNs, advancing the process of guiding hESCs to states serving inner‐ear cell‐replacement therapies and possible next‐generation hybrid auditory prostheses. © Stem Cells Translational Medicine 2017;6:923–936

The Use of Hyperbaric Oxygen Therapy in Idiopathic Sensorineural Hearing Loss: A Case Study

Idiopathic sudden sensorineural hearing loss (ISSHL) is an otologic emergency that can provoke anxiety in the patient and can be clinically challenging for the practitioner. The natural history of the condition can be as varied as its possible etiologies. Adding to the clinical challenge is the current debate of treatment modalities available. In what follows, we provide a case detailing our treatment course, including the novel use of hyperbaric oxygen therapy (HBOT) as an emerging therapy for sensorineural hearing loss. Additionally, we provide a brief review of the current state of treatment options available in the armament for ISSHL. As no identifying information is contained in our discussion, we believe the privacy of the patient has been protected and, as such, feel our manuscript is exempt from prior Institutional Review Board (IRB) approval.

Establishment of a model of cochlear lesions in rats to study potential gene therapy for sensorineural hearing loss

IntroductionSensorineural hearing loss seriously influences a patient's daily life, and no effective treatments exist to date. Gene therapy is a potential treatment for regenerating hair cells to restore hearing. MethodsIn this study, we established a cochlear lesions model to study hair cell regeneration by co-administration of kanamycin and furosemide. After the injections, we assessed the survival of outer hair cells (OHC), inner hair cells (IHC), supporting cells (SC), spiral ganglion neurons (SGN) and peripheral axons. Moreover, we used two viral vectors to detect the transgene distribution. ResultsOur results showed at 12h post-treatment, numerous OHC were missing in the basal turn. At 24h post-treatment, all OHCs in basal half of the cochlea were lost, and by 48h, OHC loss had spread to the apical coil. Four days after the injections, all OHCs were absent. At 1mo post-treatment, the organ of Corti had collapsed. In contrast, most of the SC remained 4d after the injections. The loss of SGN and peripheral axons was consistent with this time course post-treatment. The results of transgene distribution suggested the correlative gene can be transferred into the organ of Corti using adenoviruses (AdV) vectors and lentiviruses (LV) vectors in our cochlear lesion model.Comparison with Existing Method(s): We assessed the details of HC death at more time point and chosen the time point for gene transfer in this model. ConclusionsWe conclude that this cochlear lesion model would be suitable for the study of hair cell regeneration.

Stem Cell Therapy for Sensorineural Hearing Loss, Still Alive?

In mammals, the auditory system, which includes the cochlea, has a very complex structure harboring many types of cells performing different functions. Among these cells are the auditory hair cells (HCs), which are terminally and well differentiated unique cells which have lost their regenerative potential after development. The auditory HCs are easily damaged by aging as well as during episodes of ototoxicity and acoustic trauma. HCs damages typically occur in the early stage of injury and can result a permanent hearing loss. Recently, there have been tremendous developments from stem cells (SCs) research involving sensorineural hearing loss, but several limitations and obstacles persist in allowing these developments from continuing onto clinical applications. This review discusses the recent advances in SC research in sensorineural hearing loss with the subsequent sections discussing the possible hurdles and limitations that currently preclude their clinical application.

Inner ear cell therapy targeting hereditary deafness by activation of stem cell homing factors.

Congenital deafness affects about 1 in 1000 children and more than half of them have a genetic background such as Connexin26 (CX26) gene mutation. Inner ear cell therapy for sensorineural hearing loss has been expected to be an effective therapy for hereditary deafness. Previously, we developed a novel strategy for inner ear cell therapy using bone marrow mesenchymal stem cells as a supplement for cochlear fibrocytes functioning for cochlear ion transport. For cell therapy targeting hereditary deafness, a more effective cell delivery system to induce the stem cells into cochlear tissue is required, because gene mutations affect all cochlear cells cochlear cells expressing genes such as GJB2 encoding CX26. Stem cell homing is one of the crucial mechanisms to be activated for efficient cell delivery to the cochlear tissue. In our study, monocyte chemotactic protein-1, stromal cell-derived factor-1 and their receptors were found to be a key regulator for stem cell recruitment to the cochlear tissue. Thus, the activation of stem cell homing may be an efficient strategy for hearing recovery in hereditary deafness.