New treatment options for hearing loss

Müller, Ulrich; Barr-Gillespie, Peter G.

doi:10.1038/nrd4533

Cited by 167 publications

(138 citation statements)

References 295 publications

(209 reference statements)

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“…13,14 Identification of AAV vectors with specificities for these cell types will allow for the specific evaluation of gene functions associated with these cell types and provide a mode of delivery of normal copies of genes as a potential therapy to treat genetic hearing loss. Among the 12 AAV serotypes studied, 10 infected neonatal inner ears and 8 infected adult inner ears.…”

Section: Discussionmentioning

confidence: 99%

“…Gene defects in any of these cell types result in genetic hearing loss. [13][14][15] For instance, mutations in MYO7A, a gene affecting hair cell function, cause Usher syndrome type IB; GJB2 mutations in supporting cells and fibrocytes are responsible for the most common form of recessive deafness known as DFNB1, and mutations in NDP affecting the function of the stria vascularis and auditory neurons give rise to a form of syndromic deafness known as Norris disease. [16][17][18] Targeting those cell types would likely require AAV with different tropisms.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes

et al. 2016

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The mammalian inner ear consists of diverse cell types with important functions. Gene mutations in these diverse cell types have been found to underlie different forms of genetic hearing loss. Targeting these mutations for gene therapy development represents a future therapeutic strategy to treat hearing loss. Adeno-associated viral (AAV) vectors have become the vector of choice for gene delivery in animal models in vivo. To identify AAV vectors that target inner ear cell subtypes, we systemically screened 12 AAV vectors with different serotypes (AAV1, 2, 5, 6, 6.2, 7, 8, 9, rh.8, rh.10, rh.39, and rh.43) that carry a reporter gene GFP in neonatal and adult mice by microinjection in vivo. We found that most AAVs infect both neonatal and adult inner ear, with different specificities and expression levels. The inner ear cochlear sensory epithelial region, which includes auditory hair cells and supporting cells, is most frequently targeted for gene delivery. Expression of the transgene is sustained, and neonatal inner ear delivery does not adversely affect hearing. Adult inner ear injection of AAV has a similar infection pattern as the younger inner ear, with the exception that outer hair cell death caused by the injection procedure can lead to hearing loss. In the adult, more so than in the neonatal mice, cell types infected and efficiency of infection are correlated with the site of injection. Most infected cells survive in neonatal and adult inner ears. The study adds to the list of AAV vectors that transduce the mammalian inner ear efficiently, providing the tools that are important to study inner ear gene function and for the development of gene therapy to treat hearing loss.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes

et al. 2016

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“…They involve typically one large effect gene and are little affected by environment. A host of single genes that impair hearing and balance have been identified by leap-frog work in mice and humans (Steel 1995;Steel and Kimberling 1996;Dror and Avraham 2010;Steel 2014;Müller and Barr-Gillespie 2015). Candidate genes identified in human pedigree mapping have been confirmed in mice by using reverse genetics, and natural gene variants that cause hearing and balance problems in mice have led to identification of genes for human disorders (e.g., Girotto et al 2014 …”

Section: Mendelian Traitsmentioning

confidence: 99%

Application of Mouse Models to Research in Hearing and Balance

Ohlemiller

Jones

Johnson

2016

JARO

107

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Laboratory mice (Mus musculus) have become the major model species for inner ear research. The major uses of mice include gene discovery, characterization, and confirmation. Every application of mice is founded on assumptions about what mice represent and how the information gained may be generalized. A host of successes support the continued use of mice to understand hearing and balance. Depending on the research question, however, some mouse models and research designs will be more appropriate than others. Here, we recount some of the history and successes of the use of mice in hearing and vestibular studies and offer guidelines to those considering how to apply mouse models.

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“… Although genetic factors contribute to almost half of all deafness cases, treatment options for genetic deafness are limited 1–5 . We developed a genome editing approach to target a dominantly inherited form of genetic deafness.…”

mentioning

confidence: 99%

“…While ~100 deafness-associated alleles have been identified, few treatments are available to slow or reverse genetic deafness 4,5 . Complementation of wild-type alleles, or silencing dominant negative mutant alleles, have shown promising results in animal models 6, 7 .…”

mentioning

confidence: 99%

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

Gao

Tao

Lamas

et al. 2017

Nature

447

346

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Although genetic factors contribute to almost half of all deafness cases, treatment options for genetic deafness are limited1–5. We developed a genome editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9:guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated in vitro and in primary fibroblasts genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like 1) Beethoven (Bth) mouse model, even though the mutant Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9:guide RNA:lipid complexes targeting the Bth allele into the cochlea of neonatal Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response (ABR) thresholds in injected ears compared with uninjected ears or ears injected with complexes that target an unrelated gene. Enhanced acoustic reflex responses were observed among injected compared to uninjected Bth/+ animals. These findings suggest protein:RNA complex delivery of target gene-disrupting agents in vivo as a potential strategy for the treatment of some autosomal dominant hearing loss diseases.

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New treatment options for hearing loss

Cited by 167 publications

References 295 publications

Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes

Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes

Application of Mouse Models to Research in Hearing and Balance

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

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