scholarly journals Refining surgical techniques for efficient posterior semicircular canal gene delivery in the adult mammalian inner ear with minimal hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jianliang Zhu ◽  
Jin Woong Choi ◽  
Yasuko Ishibashi ◽  
Kevin Isgrig ◽  
Mhamed Grati ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Gene Delivery ◽  
Inner Ear ◽  
Semicircular Canal ◽  
Adult Mouse ◽  
Surgical Techniques ◽  
Outer Hair Cells ◽  
Dependent Manner ◽  
Posterior Semicircular Canal

AbstractHearing loss is a common disability affecting the world’s population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that although AAV2.7m8 has a lower hair cell transduction rate in adult mice compared to neonatal mice at equivalent viral load, AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency in a dose-dependent manner.

Posterior Semicircular Canal Gene Delivery in the Adult Mammalian Inner Ear

2021 ◽  
Author(s):  
Jianliang Zhu ◽  
Jin Woong Choi ◽  
Yasuko Ishibashi ◽  
Kevin Isgrig ◽  
Mhamed Grati ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Gene Delivery ◽  
Inner Ear ◽  
Semicircular Canal ◽  
Adult Mouse ◽  
High Efficiency ◽  
Outer Hair Cells ◽  
Surgical Trauma ◽  
Posterior Semicircular Canal

Abstract Hearing loss is a common disability affecting the world’s population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. The posterior semicircular canal approach has been shown to be an effective gene delivery method in the neonatal mouse inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We observe that the adult mouse inner ear is more susceptible to surgical trauma. We also find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency.

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.

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 Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3626
Author(s):  
Yi-Chun Lin ◽  
Yuan-Yung Lin ◽  
Hsin-Chien Chen ◽  
Chao-Yin Kuo ◽  
Ai-Ho Liao ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Growth Factor ◽  
Inner Ear ◽  
Outer Hair Cells ◽  
Round Window Membrane ◽  
Insulin Like Growth Factor ◽  
Noise Induced Hearing Loss ◽  
Ear Diseases ◽  
Brainstem Response ◽  
Ultrasound Microbubbles

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

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 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 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.

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