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 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 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 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 How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

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

Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa

2016 ◽  
Vol 12 (8) ◽  
pp. 2251-2260 ◽  
Author(s):  
Andrea Pensado ◽  
Francisco J. Diaz-Corrales ◽  
Berta De la Cerda ◽  
Lourdes Valdés-Sánchez ◽  
Ana Aramburu del Boz ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Retinitis Pigmentosa ◽  
Viral Vectors

scholarly journals Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1216
Author(s):  
Seigo Kimura ◽  
Hideyoshi Harashima
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Neurological Disorders ◽  
Viral Vectors ◽  
New Drugs ◽  
Brain Targeting ◽  
Current Status ◽  
Great Promise ◽  
Targeted Gene Delivery ◽  
The Central Nervous System

The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such neurological disorders are serious costly diseases that have a significant impact on society, both globally and socially. Gene therapy has great promise for the treatment of neurological disorders, but only a few gene therapy drugs are currently available. Delivery to the brain is the biggest hurdle in developing new drugs for the central nervous system (CNS) diseases and this is especially true in the case of gene delivery. Nanotechnologies such as viral and non-viral vectors allow efficient brain-targeted gene delivery systems to be created. The purpose of this review is to provide a comprehensive review of the current status of the development of successful drug delivery to the CNS for the treatment of CNS-related disorders especially by gene therapy. We mainly address three aspects of this situation: (1) blood-brain barrier (BBB) functions; (2) adeno-associated viral (AAV) vectors, currently the most advanced gene delivery vector; (3) non-viral brain targeting by non-invasive methods.

Bioreducible, hydrolytically degradable and targeting polymers for gene delivery

2017 ◽  
Vol 5 (18) ◽  
pp. 3253-3276 ◽  
Author(s):  
Ihsan Ullah ◽  
Khan Muhammad ◽  
Mary Akpanyung ◽  
Abdelilah Nejjari ◽  
Agnaldo Luis Neve ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Synthetic Gene ◽  
Suitable Alternative ◽  
Gene Carriers ◽  
Promising Application

Recently, synthetic gene carriers have been intensively developed owing to their promising application in gene therapy and considered as a suitable alternative to viral vectors because of several benefits.

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