Acta Oto-Laryngologica, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 6
Published: Dec. 30, 2024
Language: Английский
Advanced Science, Journal Year: 2024, Volume and Issue: 11(29)
Published: May 29, 2024
Abstract Mammalian cochlear hair cells (HCs) are essential for hearing, and damage to HCs results in severe hearing impairment. Damaged can be regenerated by neighboring supporting (SCs), thus the functional regeneration of is main goal restoration auditory function vivo. Here, SC trans‐differentiation into outer inner HC induced expression key transcription factors Atoh1 its co‐regulators Gfi1, Pou4f3, Six1 (GPAS), which necessary SCs that destined development maturation via AAV‐ie targeting ear stem successfully achieved. Single‐cell nuclear sequencing lineaging tracing showed majority new Atoh1‐derived a state initiating differentiation, while GP (Gfi1, Pou4f3) GPS Six1) enhanced Atoh1‐induced HCs. Moreover, patch‐clamp analysis indicated newborn GPAS forced have similar electrophysiological characteristics those native Also, induce HC‐damaged mice model. In summary, study demonstrates AAV‐mediated co‐regulation multiple genes, such as GPAS, an effective means achieve mouse cochlea.
Language: Английский
Citations
21
Advanced Science, Journal Year: 2023, Volume and Issue: 11(3)
Published: Nov. 28, 2023
Abstract OTOF mutations are the principal causes of auditory neuropathy. There reports on Otof ‐related gene therapy in mice, but there is no preclinical research drug evaluations. Here, Anc80L65 and mouse hair cell‐specific Myo15 promoter (mMyo15) used to selectively effectively deliver human cells mice nonhuman primates evaluate efficacy safety drugs. A new dual‐AAV ‐OTOF‐ hybrid strategy transfer full‐length generated, which can stably restore hearing adult p.Q939*/Q939* with profound deafness, longest duration being at least 150 days, best therapeutic effect without difference from wild‐type mice. An AAV microinjection method into cochlea cynomolgus monkeys impairment further established found be safely driven by mMyo15 cells. In addition, dose drugs has impact normal does not cause significant systemic toxicity both primates. summary, this study develops a potential for DFNB9 patients clinic provides complete, standardized, systematic data clinical application.
Language: Английский
Citations
24
Advanced Science, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 18, 2024
Abstract Hereditary deafness is the most prevalent sensory deficit disorder, with over 100 identified deafness‐related genes. Clinical treatment options are currently limited to external devices like hearing aids and cochlear implants. Gene therapy has shown promising results in various genetic disorders emerged as a potential for hereditary deafness. It successfully restored function >20 types of model mice can almost completely cure patients autosomal recessvie 9 (DFNB9) caused by OTOFERLIN ( OTOF ) mutation, thus serving translational paradigm gene other forms However, due complexity inner ear structure, diverse nature genes, variations transduction efficiency among different cells targeted adeno‐associated virus (AAV), precision approaches required This review provides comprehensive overview deafness, including preclinical studies recent research advancements this field well challenges associated AAV‐mediated therapy.
Language: Английский
Citations
10
Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)
Published: April 2, 2025
Exposure to traumatic noise triggers cochlear damage and consequently causes permanent sensorineural hearing loss. However, effective treatment strategies for noise-induced loss (NIHL) are lacking. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that plays critical role in multiple physiological pathological events. its NIHL pathogenesis remains elusive. This study revealed SIRT1 expression the cochlea progressively decreases mouse model of NIHL. Hair cell-specific knockout exacerbates outer inner hair cell synaptic ribbons, retraction nerve terminals, oxidative stress, leading more severe Conversely, adeno-associated virus (AAV)-mediated overexpression effectively attenuated most alleviated Transcriptomic analysis deficiency impairs glucose metabolism inhibits antioxidant pathways following exposure noise. Further investigation exerts an effect, at least part, through AMPK activation cultured auditory HEI-OC1 cells exposed stress. Collectively, these findings indicate essential maintenance redox balance mitochondrial function after exposure, thus providing promising therapeutic target treatment.
Language: Английский
Citations
1
Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113728 - 113728
Published: April 1, 2025
Language: Английский
Citations
1
Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18
Published: Jan. 24, 2024
Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis auditory development growing compendium deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered relatively secure vector in clinical trials, can deliver various transgenes based strategies such as replacement, silencing, editing, or addition to alleviate diverse types SNHL. This review delved preclinical advances AAV-based SNHL, spanning hereditary acquired types. Particular focus is placed dual-AAV construction method its application, delivery route mouse inner ear models (local, systemic, fetal, cerebrospinal fluid administration), significant considerations transforming animal model implementation.
Language: Английский
Citations
6
Journal of Audiology & Otology, Journal Year: 2024, Volume and Issue: 28(2), P. 88 - 92
Published: April 10, 2024
Sensorineural hearing loss (SNHL) is the most common sensory disorder, with a high Mendelian genetic contribution. Considering genotypic and phenotypic heterogeneity of SNHL, advent next-generation sequencing technologies has revolutionized knowledge on its genomic architecture. Nonetheless, conventional application panel exome in real-world practice being challenged by emerging need to explore diagnostic capability whole-genome sequencing, which enables detection both noncoding structural variations. Small molecules gene therapies represent good examples how breakthroughs understanding can be translated into targeted for SNHL. For example, small have been used ameliorate autoinflammatory caused gain-of-function variants NLRP3 inner ear proteinopathy OSBPL2 underlying dysfunctional autophagy. Strikingly, successful outcomes first-in-human trial OTOF therapy highlighted potential treatment various forms loss. clustered regularly interspaced short palindromic repeats (CRISPR)-based are currently developed site-specific genome editing treat human disorders. These advancements led an era genotype- mechanism-based precision medicine SNHL practice.
Language: Английский
Citations
4
Advanced Biology, Journal Year: 2024, Volume and Issue: 8(10)
Published: July 15, 2024
Abstract For monogenic genetic diseases, in utero gene therapy (IUGT) shows the potential for early prevention against irreversible and lethal pathological changes. Moreover, animal models have also demonstrated effectiveness of IUGT treatment coagulation disorders, hemoglobinopathies, neurogenetic metabolic pulmonary diseases. major alpha thalassemia severe osteogenesis imperfecta, stem cell transplantation has entered phase I clinical trial stage. Within realm inner ear, hearing loss significantly hampers speech, cognitive, intellectual development children. Nowadays, therapies offer substantial promise deafness, with success trials autosomal recessive deafness 9 using AAV‐OTOF therapy. However, majority mutations that cause affect cochlear structures before birth fetuses. Thus, alterations structure leading to promising applications. In this review, addressing advances various fields IUGT, progress, application are focused, particular its implementation methods unique advantages.
Language: Английский
Citations
4
Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 31, 2025
Human genome analyses have revealed that abnormal BAF (BRG1/BRM-associated factor) complex is highly associated with hearing loss. However, the underlying pathogenesis remains largely unknown. Disrupted structure and function of organ Corti most prevalent cause sensorineural loss in mammals. Here, we investigated role Brg1-based during differentiation development auditory sensory epithelium, a crucial period for formation Corti. Our findings indicate deletion Brg1 leads to premature hair cell (HC) by inactivating Sonic hedgehog (Shh) signaling. Despite HCs, subsequent inner cells (IHCs) outer (OHCs) was impaired. Additionally, observed mosaic-like arrangement HCs supporting (SCs) disrupted resulting epithelium patterning. Furthermore, found planar polarity Brg1-deficient cochlea abnormal. study demonstrates pivotal patterning
Language: Английский
Citations
0
Advanced Therapeutics, Journal Year: 2025, Volume and Issue: unknown
Published: May 16, 2025
Abstract Hearing loss (HL) is a significant global health challenge, affecting billions of people and severely impacting quality life. While traditional interventions such as hearing aids cochlear implants mitigate symptoms, they fail to address the underlying causes HL, especially in cases involving severe damage hair cells or spiral ganglion neurons. Emerging therapeutic strategies, including biomaterials, nanocarrier drug delivery systems, gene therapy, extracellular vesicle (EV)‐based approaches, have demonstrated potential promoting inner ear regeneration restoring auditory function. Biomaterials mimic matrix guide cell regeneration, while nanocarriers EVs enhance targeted sustained agents. Gene therapy offers opportunities correct genetic mutations, addressing hereditary HL. However, challenges anatomical complexity cochlea, blood‐labyrinth barrier, limited regenerative capacity persist. Future research must focus on scalable, biocompatible, clinically safe systems advance clinical translation these innovative therapies. This review underscores integrating strategies develop effective long‐lasting treatments for
Language: Английский
Citations
0