Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time po...

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Published inMolecular therapy Vol. 27; no. 3; pp. 681 - 690
Main Authors Yoshimura, Hidekane, Shibata, Seiji B., Ranum, Paul T., Moteki, Hideaki, Smith, Richard J.H.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 06.03.2019
Elsevier Limited
American Society of Gene & Cell Therapy
Subjects
adeno-associated virus
Age
Animal models
Animals
Cell survival
Cochlea
Cochlea - metabolism
Cochlea - physiopathology
Cochlea - ultrastructure
Cytomegalovirus
Deafness
Deafness - genetics
Deafness - physiopathology
Degeneration
Dependovirus - genetics
Disease Models, Animal
Ear
Ear, Inner - metabolism
Ear, Inner - physiopathology
Ear, Inner - ultrastructure
Ears & hearing
Gene silencing
Gene therapy
Genetic Therapy
Genetic Vectors - genetics
Gestational age
Hearing loss
Hearing Loss - genetics
Hearing Loss - physiopathology
Humans
Immunohistochemistry
inner ear
Maturation
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Inbred C3H
MicroRNAs
Microscopy, Electron, Scanning
miRNA
Neonates
Organ of Corti
Original
Quality of life
RNA Interference
RNA-mediated interference
Scanning electron microscopy
Studies
vestibule
Vestibule, Labyrinth - metabolism
Vestibule, Labyrinth - physiopathology
Vestibule, Labyrinth - ultrastructure
United States > US
cochlea
gene therapy
adeno-associated virus
vestibule
hearing loss
inner ear
Online AccessGet full text
ISSN1525-0016
1525-0024
1525-0024
DOI10.1016/j.ymthe.2018.12.014

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Abstract Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects. Smith and colleagues demonstrate the effect of cochlear gene therapy in an adult murine model of human TMC1 deafness and show that RNAi-mediated gene silencing slows progression of hearing loss, suggesting a significant step toward its application in human subjects.
AbstractList Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects.
Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects.Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects.
Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects. Smith and colleagues demonstrate the effect of cochlear gene therapy in an adult murine model of human TMC1 deafness and show that RNAi-mediated gene silencing slows progression of hearing loss, suggesting a significant step toward its application in human subjects.
Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects. Smith and colleagues demonstrate the effect of cochlear gene therapy in an adult murine model of human TMC1 deafness and show that RNAi-mediated gene silencing slows progression of hearing loss, suggesting a significant step toward its application in human subjects.
Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects.
Author Moteki, Hideaki
Shibata, Seiji B.
Ranum, Paul T.
Smith, Richard J.H.
Yoshimura, Hidekane
AuthorAffiliation 1 Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
2 Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
3 Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
AuthorAffiliation_xml – name: 2 Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
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  fullname: Yoshimura, Hidekane
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  organization: Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30686588$$D View this record in MEDLINE/PubMed
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2019. The American Society of Gene and Cell Therapy
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Issue 3
Keywords cochlea
gene therapy
adeno-associated virus
vestibule
hearing loss
inner ear
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Snippet Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of...
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SubjectTerms adeno-associated virus
Age
Animal models
Animals
Cell survival
Cochlea
Cochlea - metabolism
Cochlea - physiopathology
Cochlea - ultrastructure
Cytomegalovirus
Deafness
Deafness - genetics
Deafness - physiopathology
Degeneration
Dependovirus - genetics
Disease Models, Animal
Ear
Ear, Inner - metabolism
Ear, Inner - physiopathology
Ear, Inner - ultrastructure
Ears & hearing
Gene silencing
Gene therapy
Genetic Therapy
Genetic Vectors - genetics
Gestational age
Hearing loss
Hearing Loss - genetics
Hearing Loss - physiopathology
Humans
Immunohistochemistry
inner ear
Maturation
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Inbred C3H
MicroRNAs
Microscopy, Electron, Scanning
miRNA
Neonates
Organ of Corti
Original
Quality of life
RNA Interference
RNA-mediated interference
Scanning electron microscopy
Studies
vestibule
Vestibule, Labyrinth - metabolism
Vestibule, Labyrinth - physiopathology
Vestibule, Labyrinth - ultrastructure
Title Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness
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Volume 27
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