Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy

Akil, Omar; Seal, Rebecca P.; Burke, K.; Wang, Chuansong; Alemi, A. Sean; During, Matthew J.; Edwards, Robert H.; Lustig, Lawrence R.

doi:10.1016/j.neuron.2012.05.019

Cited by 316 publications

(368 citation statements)

References 39 publications

(57 reference statements)

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“…Prior studies had shown some transduction of IHCs with conventional AAVs, but little transduction of OHCs. 12,23 We found that exo-AAV1 efficiently transduces IHCs and transduces OHCs much more efficiently than does conventional AAV1. AAV1 was our standard of comparison because it has been used in prior studies of hearing gene therapy.…”

Section: Discussionmentioning

confidence: 89%

“…AAV1 was our standard of comparison because it has been used in prior studies of hearing gene therapy. 12,13 In those studies, it was shown to only transduce inner hair cells relatively efficiently. Interestingly, we found that exo-AAV9-GFP was extremely efficient at transduction of cochlear explant cultures, although, in vivo, this serotype performed similarly to exo-AAV1.…”

Section: Discussionmentioning

confidence: 99%

“…Adenoassociated virus (AAV) vectors are presently the most promising vectors for cochlear gene delivery, but in vivo transduction is mostly limited to IHCs. In previous studies, 12,13 virtually no OHCs were transduced by AAV vectors after in vivo injection in mice. Similarly, it is difficult to express genes in hair cells in vitro for research, which has slowed characterization of proteins involved in hair cell function.…”

Section: Introductionmentioning

confidence: 94%

“…12,13 We therefore prepared exo-AAV1 and conventional AAV1. AAV1 and exo-AAV1 were isolated from the lysate and culture medium of vector-producing 293T cells, respectively ( Figure 1A; see Materials and Methods).…”

Section: Aav1 Associates With Exosomes When Vectors Are Isolated Frommentioning

confidence: 99%

“…We therefore compared conventional AAV1 and exo-AAV1 in vivo using direct injections into P0/P1 mouse cochleas. We compared two injection routes: through the round window membrane (RWM) into the scala tympani (used in two animal models of hereditary deafness 12,13 ), and through the lateral wall of the cochlea by cochleostomy at the basal turn. In both cases, 250 nL of virus-containing solution was injected over $10 min.…”

Section: Exo-aav Outperforms Conventional Aav In Transgene Delivery Tmentioning

confidence: 99%

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Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

et al. 2017

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Aav1 Associates With Exosomes When Vectors Are Isolated Frommentioning

confidence: 99%

Section: Exo-aav Outperforms Conventional Aav In Transgene Delivery Tmentioning

confidence: 99%

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Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

et al. 2017

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Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

Qi,

Zhang,

Tan

et al. 2023

Advanced Science

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OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

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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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Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy

Cited by 316 publications

References 39 publications

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

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

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