scholarly journals Gene therapy for hearing loss

2019 ◽  
Vol 28 (R1) ◽  
pp. R65-R79 ◽  
Author(s):  
Ryotaro Omichi ◽  
Seiji B Shibata ◽  
Cynthia C Morton ◽  
Richard J H Smith
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Inner Ear ◽  
Viral Vectors ◽  
Therapeutic Potential ◽  
Late Onset ◽  
Science Research ◽  
Gene Replacement ◽  
Age Related ◽  
Genetic And Environmental Factors

Abstract Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.

scholarly journals Inner Ear Gene Therapy in Mouse Models of Genetic Hearing Loss

2021 ◽  
Vol 64 (4) ◽  
pp. 215-222
Author(s):  
Jin Woong Choi
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Gene Delivery ◽  
Inner Ear ◽  
Mouse Models ◽  
Viral Vectors ◽  
Gene Replacement ◽  
Physiological Mechanisms ◽  
Surgical Methods ◽  
Genetic Hearing Loss

Hearing loss is the most frequent sensory disorder affecting newborns and children. About 1 newborn in every 500 suffer from congenital hearing loss, with approximately half of these having a genetic cause. In the last few decades, the study of genetic hearing loss and related mouse models has unveiled molecular, cellular, and physiological mechanisms of the disease. In addition, effective and safe viral vectors for gene delivery to the inner ear have been generated. A growing number of approaches, including gene replacement, gene silencing, and gene editing, have proved effective in mouse models. This article briefly introduces basic strategies of gene therapy, viral vectors used and surgical methods for gene delivery, and reviews the current works on mouse modes of genetic hearing loss.

An Update on Ocular Gene Therapy for Monogenic and Multifactorial Retinal Diseases

2019 ◽  
Vol 3 (5) ◽  
pp. 366-377
Author(s):  
Alice Y. Hou ◽  
Szilárd Kiss
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Gene Replacement ◽  
Age Related Macular Degeneration ◽  
Great Promise ◽  
Retinal Diseases ◽  
Multifactorial Diseases ◽  
Monogenic Disorders ◽  
Age Related ◽  
Augmentation Strategy

Monogenic and multifactorial retinal diseases are genetically and clinically diverse conditions that have historically shared an untreatable clinical course. In recent years, the advent of targeted treatments like gene therapy has enabled intraocular delivery of viral vectors, such as adeno-associated viruses and retroviruses, that establish long-term stable protein expression. Despite the innate distinctions between mainly monogenic disorders affecting the retina such as Leber congenital amaurosis (LCA), heterogeneous monogenic conditions like retinitis pigmentosa (RP), and multifactorial diseases such as age-related macular degeneration (AMD), gene therapy has shown great promise as a gene replacement or augmentation strategy to treat or halt these disorders. This review will present an overview of retinal gene therapy and provide a comprehensive analysis of past and current clinical trials for LCA, RP, and AMD. It will discuss the paradigm shift that has occurred in ophthalmic care thanks to the development of gene therapy, as well as its challenges for the future.

scholarly journals Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuewen Wu ◽  
Li Zhang ◽  
Yihui Li ◽  
Wenjuan Zhang ◽  
Jianjun Wang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Inner Ear ◽  
Viral Vectors ◽  
Survival Rates ◽  
Semicircular Canals ◽  
Dependent Manner ◽  
Syndrome Type ◽  
Dose Dependent

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

scholarly journals Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

2021 ◽  
Vol 21 ◽  
pp. 209-236
Author(s):  
Kamakshi Bankoti ◽  
Charles Generotti ◽  
Tiffany Hwa ◽  
Lili Wang ◽  
Bert W. O’Malley ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Inner Ear ◽  
Sensorineural Hearing

scholarly journals mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss

2021 ◽  
Vol 22 (12) ◽  
pp. 6368
Author(s):  
Maurizio Cortada ◽  
Soledad Levano ◽  
Daniel Bodmer
Keyword(s):  
Hearing Loss ◽  
Cell Survival ◽  
Inner Ear ◽  
Hearing Aids ◽  
Noise Exposure ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Curative Therapy ◽  
Age Related ◽  
Survival Pathways

Hearing loss affects many people worldwide and occurs often as a result of age, ototoxic drugs and/or excessive noise exposure. With a growing number of elderly people, the number of people suffering from hearing loss will also increase in the future. Despite the high number of affected people, for most patients there is no curative therapy for hearing loss and hearing aids or cochlea implants remain the only option. Important treatment approaches for hearing loss include the development of regenerative therapies or the inhibition of cell death/promotion of cell survival pathways. The mammalian target of rapamycin (mTOR) pathway is a central regulator of cell growth, is involved in cell survival, and has been shown to be implicated in many age-related diseases. In the inner ear, mTOR signaling has also started to gain attention recently. In this review, we will emphasize recent discoveries of mTOR signaling in the inner ear and discuss implications for possible treatments for hearing restoration.

scholarly journals Effects of Microbubble Size on Ultrasound-Mediated Gene Transfection in Auditory Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Ai-Ho Liao ◽  
Yi-Lei Hsieh ◽  
Hsin-Chiao Ho ◽  
Hang-Kang Chen ◽  
Yi-Chun Lin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Gene Transfer ◽  
Inner Ear ◽  
Hair Cells ◽  
Gene Transfection ◽  
Effective Technique ◽  
Size Dependent ◽  
Genes Encoding

Gene therapy for sensorineural hearing loss has recently been used to insert genes encoding functional proteins to preserve, protect, or even regenerate hair cells in the inner ear. Our previous study demonstrated a microbubble- (MB-)facilitated ultrasound (US) technique for delivering therapeutic medication to the inner ear. The present study investigated whether MB-US techniques help to enhance the efficiency of gene transfection by means of cationic liposomes on HEI-OC1 auditory cells and whether MBs of different sizes affect such efficiency. Our results demonstrated that the size of MBs was proportional to the concentration of albumin or dextrose. At a constant US power density, using 0.66, 1.32, and 2.83 μm albumin-shelled MBs increased the transfection rate as compared to the control by 30.6%, 54.1%, and 84.7%, respectively; likewise, using 1.39, 2.12, and 3.47 μm albumin-dextrose-shelled MBs increased the transfection rates by 15.9%, 34.3%, and 82.7%, respectively. The results indicate that MB-US is an effective technique to facilitate gene transfer on auditory cellsin vitro. Such size-dependent MB oscillation behavior in the presence of US plays a role in enhancing gene transfer, and by manipulating the concentration of albumin or dextrose, MBs of different sizes can be produced.

scholarly journals Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

2017 ◽  
Vol 114 (36) ◽  
pp. 9695-9700 ◽  
Author(s):  
Alice Emptoz ◽  
Vincent Michel ◽  
Andrea Lelli ◽  
Omar Akil ◽  
Jacques Boutet de Monvel ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Inner Ear ◽  
Usher Syndrome ◽  
Vestibular Function ◽  
Gene Replacement ◽  
Syndrome Type ◽  
Mechanoelectrical Transduction ◽  
Efficient Gene ◽  
Usher Syndrome Type

Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.

scholarly journals Gene Replacement Therapy: A Primer for the Health-system Pharmacist

2019 ◽  
Vol 33 (6) ◽  
pp. 846-855 ◽  
Author(s):  
John Petrich ◽  
Dominic Marchese ◽  
Chris Jenkins ◽  
Michael Storey ◽  
Jill Blind
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Expert Opinion ◽  
Viral Vectors ◽  
Professional Associations ◽  
The United States ◽  
Gene Replacement ◽  
World Health ◽  
Risk Level ◽  
Gene Replacement Therapy

Purpose: Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. Summary: There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. Conclusion: Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.

scholarly journals Experimental Study of Local Inner Ear Gene Therapy for Controlling Autoimmune Sensorineural Hearing Loss

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Chang-qiang Tan ◽  
Xia Gao ◽  
Wen-jun Cai ◽  
Xiao-yun Qian ◽  
Ling Lu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Inner Ear ◽  
Recombinant Adenovirus ◽  
Adenovirus Vector ◽  
Sensorineural Hearing ◽  
Spiral Ligament ◽  
Small Blood Vessel ◽  
Recombinant Adenovirus Vector

This study aimed to investigate the efficacy of gene therapy for treating autoimmune sensorineural hearing loss (ASHL) via local administration of a recombinant adenovirus vector containing the Fas ligand or interleukin IL-10 gene. Guinea pigs were divided into four groups, with different microinjections in the scala tympani. Group A were injected with FasL-EGFP, B with IL-10-EGFP, C with EGFP, and D with artificial perilymph. Seven days later, auditory brain-stem response (ABR) was tested, and the temporal bone was stained and observed by light microscopy. The spiral ligament and basement membrane were observed using transmission electron microscopy. FasL and IL-10 expression were examined using immunofluorescence histochemistry. Immunohistochemical analysis showed that the recombinant adenovirus vector in Groups A, B, and C can transfect the stria vascularis, the spiral ligament, the organ of Corti, the spiral ganglion, the region surrounding the small blood vessel in the modiolus, and the cochlear bone wall. Compared with those in Groups C and D, the ABR wave III mean thresholds were significantly lower and the inner ear immunoinflammatory responses in Groups A and B were significantly alleviated. Inhibition of immunoinflammatory response alleviated immunoinflammatory injury and auditory dysfunction. This technique shows potential as a novel therapy for ASHL.

Expression Profiling of MicroRNAs in the Inner Ear of Elderly People by Real-Time PCR Quantification

2017 ◽  
Vol 22 (3) ◽  
pp. 135-145 ◽  
Author(s):  
Kuwon Sekine ◽  
Tomohiro Matsumura ◽  
Toshihiro Takizawa ◽  
Yurika Kimura ◽  
Shiho Saito ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Real Time Pcr ◽  
Expression Profiling ◽  
Molecular Mechanisms ◽  
Elderly Subjects ◽  
Age Related ◽  
Inner Ear Development ◽  
Temporal Bones ◽  
Age Related Hearing Loss

The molecular mechanisms underlying age-related hearing loss are unknown, and currently, there is no treatment for this condition. Recent studies have shown that microRNAs (miRNAs) and age-related diseases are intimately linked, suggesting that some miRNAs may present attractive therapeutic targets. In this study, we obtained 8 human temporal bones from 8 elderly subjects at brain autopsy in order to investigate the expression profile of miRNAs in the inner ear with miRNA arrays. A mean of 478 different miRNAs were expressed in the samples, of which 348 were commonly expressed in all 8 samples. Of these, levels of 16 miRNAs significantly differed between young elderly and old elderly subjects. miRNAs, which play important roles in inner ear development, were detected in all samples, i.e., in both young and old elderly subjects, whether with or without hearing loss. Our results suggest that these miRNAs play important roles not only in development, but also in the maintenance of inner ear homeostasis.

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