RNA Interference Prevents Autosomal-Dominant Hearing Loss

Shibata, Seiji; Ranum, Paul T.; Moteki, Hideaki; Pan, Bifeng; Goodwin, Alexander T.; Goodman, Shawn S.; Abbas, Paul J.; Holt, Jeffrey R.; Smith, Richard J.H.

doi:10.1016/j.ajhg.2016.03.028

Cited by 107 publications

(97 citation statements)

References 37 publications

(64 reference statements)

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“…Our results suggest the potential of such an approach for the treatment of autosomal dominant hearing loss diseases related to hair cell dysfunction, and provide a complementary strategy to other approaches that use antisense oligos (ASO) or RNA interference 6, 25 . The genome editing strategy developed here may inform the future development of a DNA-free, virus-free, one-time treatment for certain genetic hearing loss disorders.…”

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confidence: 73%

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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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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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confidence: 73%

“…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 .…”

mentioning

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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446

346

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“…The end product of this incompletely understood process (Lu and Sipe, 2016; Schüler et al, 2013) is a highly polarized cell that allows mechanical stimuli to exert changes on the cell’s resting potential depending on the direction of the stimulation (Fig. 1) through opening of channels attached to tip links [putative candidates are TMC1/2 (Shibata et al, 2016; Wu and Müller, 2016)]. Many mechano-sensitive cells display a permutation of this common scheme of kinocilia/microvilli.…”

Section: Introductionmentioning

confidence: 99%

“…It would be important to establish how the stereocilin-mediated connections of stereocilia molecularly relate to the microvilli connections in choanoflagellates and sponges. This could help to reveal the evolutionary origin of the leading candidates for the mechanosensory transduction channel, TMC1/2 (Shibata et al, 2016) and TMHS/TMIE (Wu et al, 2016; Wu and Müller, 2016). …”

Section: Introductionmentioning

confidence: 99%

Gene, cell, and organ multiplication drives inner ear evolution

Fritzsch

Elliott

2017

Developmental Biology

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We review the development and evolution of the ear neurosensory cells, the aggregation of neurosensory cells into an otic placode, the evolution of novel neurosensory structures dedicated to hearing and the evolution of novel nuclei and their input dedicated to processing those novel auditory stimuli. The evolution of the apparently novel auditory system lies in duplication and diversification of cell fate transcription regulation that allows variation at the cellular level [transforming a single neurosensory cell into a sensory cell connected to its targets by a sensory neuron as well as diversifying hair cells], organ level [duplication of organ development followed by diversification and novel stimulus acquisition] and brain nuclear level [multiplication of transcription factors to regulate various neuron and neuron aggregate fate to transform the spinal cord into the unique hindbrain organization]. Tying cell fate changes driven by bHLH and other transcription factors into cell and organ changes is at the moment tentative as not all relevant factors are known and their gene regulatory network is only rudimentary understood. Future research can use the blueprint proposed here to provide both the deeper molecular evolutionary understanding as well as a more detailed appreciation of developmental networks. This understanding can reveal how an auditory system evolved through transformation of existing cell fate determining networks and thus how neurosensory evolution occurred through molecular changes affecting cell fate decision processes. Appreciating the evolutionary cascade of developmental program changes could allow identifying essential steps needed to restore cells and organs in the future.

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“…In genetic investigation of deafness locus of human autosomal the two families had a common point mutation in seed sequence which was transferred to mature miRNA and cause loss of miRNA function. Knocking down miR-183 family members cause defect in semicircular canals and inner ear [51]. …”

Section: Mir-183 Family Activity In Hair Cellmentioning

confidence: 99%

MicroRNA-183 Family in Inner Ear: Hair Cell Development and Deafness

sani

Hashemzadeh‐Chaleshtori

Saidijam

et al. 2016

J Audiol Otol

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miRNAs are essential factors of an extensively conserved post-transcriptional process controlling gene expression at mRNA level. Varoius biological processes such as growth and differentiation are regulated by miRNAs. Web of Science and PubMed databases were searched using the Endnote software for the publications about the role miRNA-183 family in inner ear: hair cell development and deafness published from 2000 to 2016. A triplet of these miRNAs particularly the miR-183 family is highly expressed in vertebrate hair cells, as with some of the peripheral neurosensory cells. Point mutations in one member of this family, miR-96, underlie DFNA50 autosomal deafness in humans and lead to abnormal hair cell development and survival in mice. In zebrafish, overexpression of the miR-183 family induces extra and ectopic hair cells, while knockdown decreases the number of hair cell. The miR-183 family (miR-183, miR-96 and miR-182) is expressed abundantly in some types of sensory cell in the eye, nose and inner ear. In the inner ear, mechanosensory hair cells have a robust expression level. Despite much similarity of these miRs sequences, small differences lead to distinct targeting of messenger RNAs targets. In the near future, miRNAs are likely to be explored as potential therapeutic agents to repair or regenerate hair cells, cell reprogramming and regenerative medicine applications in animal models because they can simultaneously down-regulate dozens or even hundreds of transcripts.

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RNA Interference Prevents Autosomal-Dominant Hearing Loss

Cited by 107 publications

References 37 publications

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

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

Gene, cell, and organ multiplication drives inner ear evolution

MicroRNA-183 Family in Inner Ear: Hair Cell Development and Deafness

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