Deafness: from genetic architecture to gene therapy

Petit, Christine; Bonnet, Crystel; Safieddine, Saaïd

doi:10.1038/s41576-023-00597-7

Cited by 35 publications

(28 citation statements)

References 211 publications

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“…Mammalian sound-receptor HCs are vulnerable to various genetic mutations, environmental ototoxic factors, and aging. HC degeneration is one of the primary reasons for human sensorineural hearing impairment [50], and several genes whose mutations lead to HC degeneration starting at different ages have been identified previously. For example, HC development is severely defective in Atoh1 -/- mutants [7, 51], and Atoh1 -/- cochlear sensory cells undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Gene therapy is a promising strategy for restoring hearing capacity in humans with inherited gene mutations causing hearing impairment [50], and a few such therapy examples have been reported to date, including Otoferlin and vGlut3 gene-replacement therapies [62–65]. Currently, therapeutic cDNAs are primarily delivered into HCs by using an adeno-associated virus (AAV) vector.…”

Section: Discussionmentioning

confidence: 99%

“…Gene therapy is a promising strategy for restoring hearing capacity in humans with inherited gene mutations causing hearing impairment [50]…”

Section: Potential Application Of the Three Rbm24 Enhancers In Cochle...mentioning

confidence: 99%

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Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

Wang

Liu

2023

Preprint

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Mammals have limited sound receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the molecular mechanisms underlying how to maintain HC survival is crucial to prevent hearing impairment. The Pou4f3-/- or Gfi1-/- HCs initially form but rapidly degenerate, whereas Rbm24-/- HCs degenerate much later. It remains elusive about the transcriptional cascades among Pou4f3, Gfi1 and Rbm24. Here, we demonstrate that Rbm24 expression is completely repressed in Pou4f3-/- HCs, but its expression is not altered in Gfi1-/- HCs. Moreover, both Pou4f3 and Gfi1 expressions are intact in Rbm24-/- HCs. Moreover, by the in vivo mouse transgenic reporter assays, we identify three Rbm24 enhancers to which Pou4f3 binds. Finally, we test whether Rbm24 restoration can alleviate degeneration of Pou4f3-/- HCs. Our in vivo genetic assay shows that ectopic Rbm24 alone is unable to stop Pou4f3-/- HCs from undergoing degeneration. Collectively, our study provides new molecular and genetic insights into how HC survival is regulated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

Wang

Liu

2023

Preprint

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“…The emergence of inner ear gene therapy using recombinant adeno-associated viral vectors (AAVs) in clinical mouse models for human deafness has established AAVs as highly effective tools for conducting conditional genetic manipulations of specific cell types within the inner ear [1][2][3]. Several proof of principle studies have shown that the use AAVs for virus mediated gene transfer to the developing inner ear is an efficient and safe strategy for gene delivery [4,5], allowing the rescue of hearing function in several mouse models for inherited congenital human deafness mice presenting mutations causing profound deafness [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Numerous AAV serotypes have already been tested mostly in neonatal and to a lesser extent in mature mouse inner ear, exhibiting different transduction rates and expression levels in specific target cells and tissues [2,10,11]. The recombinant serotypes AAV-PHP.eB and AAV-DJ target the two major cochlear cell types, the sensory hair cells and the supporting cells, respectively, with remarkably high efficiency and specificity when administered at neonatal stages [12].…”

Section: Introductionmentioning

confidence: 99%

In uteroadeno-associated virus (AAV)-mediated gene delivery targeting sensory and supporting cells in the embryonic mouse inner ear

Barbosa-Spinola,

Boutet de Monvel,

Safieddine

et al. 2024

Preprint

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In vivo gene delivery to tissues using adeno-associated vector (AAVs) has revolutionized the field of gene therapy. Yet, while sensorineural hearing loss is one of the most common sensory disorders worldwide, gene therapy applied to the human inner ear is still in its infancy. Recent advances in the development recombinant AAVs have significantly improved their cell tropism and transduction efficiency across diverse inner ear cell types to a level that renders this tool valuable for conditionally manipulating gene expression in the context of developmental biology studies of the mouse inner ear. Here, we describe a protocol for in utero micro-injection of AAVs into the embryonic inner ear, using the AAV-PHP.eB and AAV-DJ serotypes that respectively target the sensory hair cells and the supporting cells of the auditory sensory epithelium. We also aimed to standardize procedures for imaging acquisition and image analysis to foster research reproducibility and allow accurate comparisons between studies. We find that AAV-PHP.eB and AAV-DJ provide efficient and reliable tools for conditional gene expression targeting cochlear sensory and supporting cells in the mouse inner ear, from late embryonic stages on.

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Inner Ear Organoids: Strengths and Limitations

Pianigiani,

Roccio

2024

JARO

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Inner ear organoids derived from differentiation of human pluripotent stem cells have recently gained momentum as tools to study inner ear development and developmental defects. An additional exciting aspect about this technology is represented by its translational potential, specifically, the use of organoids to validate therapeutics for hearing and balance restoration on human/patient-specific cells. This latter aspect will be briefly discussed here including opportunities and current limitations.

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Deafness: from genetic architecture to gene therapy

Cited by 35 publications

References 211 publications

Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

In uteroadeno-associated virus (AAV)-mediated gene delivery targeting sensory and supporting cells in the embryonic mouse inner ear

Inner Ear Organoids: Strengths and Limitations

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