Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c

Pan, Bifeng; Askew, Charles; Galvin, Alice; Heman‐Ackah, Selena E.; Asai, Yukako; Indzhykulian, Artur A.; Jodelka, Francine M.; Hastings, Michelle L.; Lentz, Jennifer J; Vandenberghe, Luk; Holt, Jeffrey R.; Géléoc, Gwenaëlle G.S.

doi:10.1038/nbt.3801

Cited by 243 publications

(253 citation statements)

References 45 publications

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“…Further studies are required to determine why the transgene injection did not fully restore cochlear function in Ush1g −/− mice. The higher rates of hair cell transduction in the vestibular end organs than in the cochlea raise the hope of a full restoration of hearing by increasing the transduction rates in the cochlear hair cells (22). It is worthy of note that hearing thresholds were significantly improved for sounds in the low-frequency range (5-15 kHz), which are analyzed in a cochlear apical region that, owing to its high curvature, cannot be reached by the electrode arrays of cochlear implants (39).…”

Section: Discussionmentioning

confidence: 99%

“…Various viral vectors containing GFP as a reporter gene have been shown to transduce inner ear hair cells (11)(12)(13)(14)(15), and several studies have investigated the use of gene therapy to restore hearing and balance in animal models, with different degrees of success. However, to date, partial hearing improvement was only obtained for mouse models without severe dysmorphogenesis of the inner ear hair cells (16)(17)(18)(19)(20)(21)(22). Here, we focused on the genetic form of USH1 caused by mutations of USH1G, encoding the submembrane scaffold protein sans (23,24).…”

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confidence: 99%

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

Emptoz

Michel

Lelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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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.gene | therapy | balance | mouse | Usher

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Emptoz

Michel

Lelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…The laboratories of Geleoc and Holt [Pan et al, 2017] reported results from a knock-in mouse model of Usher syndrome type 1C. They delivered a synthetic AAV vector, Anc80L65, containing wild type Ush1c into the inner ear of Ush1c c.216G>A mutant mice.…”

Section: General Progress In Treating Hereditary Deafnessmentioning

confidence: 99%

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

Choo

Tawfik

Martin

et al. 2017

American J of Med Genetics Pt C

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The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

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“…Complementation of wild-type alleles, or silencing dominant negative mutant alleles, have shown promising results in animal models 6, 7 . Nonetheless, current approaches face potential challenges including immunogenicity, oncogenicity, and limitations of viral vectors 8,9 .…”

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confidence: 99%

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

Gao

Tao

Lamas

et al. 2017

Nature

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427

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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Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c

Cited by 243 publications

References 45 publications

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

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

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

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

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