The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

Human Genetics, Journal Year: 2022, Volume and Issue: 141(3-4), P. 709 - 735

Published: March 30, 2022

Abstract Usher syndrome (USH) is the most common cause of deaf–blindness in humans, with a prevalence about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are currently used to reduce burden hearing loss severe-to-profoundly deaf patients, but many promising treatments including gene, cell, and drug therapies restore native function inner ear retinal sensory cells under investigation. The traditional clinical classification defines three major subtypes—USH1, 2 3—according severity onset, presence or absence vestibular dysfunction, age at onset retinitis pigmentosa. Pathogenic variants nine USH genes have been initially reported: MYO7A, USH1C, PCDH15, CDH23 , USH1G for USH1, USH2A, ADGRV1, WHRN USH2, CLRN1 USH3. Based on co-occurrence vision deficits, list has extended few other genes, limited supporting information. A consensus combined criteria crucial development accurate diagnosis improve patient management. In recent years, wealth information obtained concerning properties proteins, related molecular networks, potential genotype–phenotype correlations, pathogenic mechanisms underlying impairment hearing, balance vision. advent precision medicine calls clear more precise syndrome, exploiting all existing data develop clinical/genetic/network/functional syndrome.

Language: Английский

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Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(2), P. 685 - 685

Published: Feb. 17, 2023

Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration retinal photoreceptors leading to visual decline. It the most common type inherited dystrophy and has high burden on both patients society. This condition causes gradual loss vision, with its typical manifestations including nyctalopia, concentric field loss, ultimately bilateral central vision loss. one disability blindness in people under 60 years old affects over 1.5 million worldwide. There currently no curative treatment for RP, only small confirmed RPE65 mutations are eligible receive gene therapy market: voretigene neparvovec. The current therapeutic armamentarium limited retinoids, vitamin A supplements, protection from sunlight, aids, medical surgical interventions treat ophthalmic comorbidities, which aim slow down progression disease. Considering such landscape, there an urgent need developing new individualized modalities targeting degeneration. Although heterogeneity involved RP makes target development difficult, recent fundamental studies showed promising progress elucidation photoreceptor mechanism. discovery novel molecule therapeutics that can selectively specific receptors or pathways will serve as solid foundation advanced drug development. article review focusing preclinical stage research molecular targets, starting point We alterations mainly those regarding endoplasmic reticulum (ER) stress apoptotic pathways, maintenance redox balance, genomic stability. then discuss approaches development, cell therapy, well literature identifying potential targets RP.

Language: Английский

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Promising Strategies for Preserving Adult Endothelium Health and Reversing Its Dysfunction: From Liquid Biopsy to New Omics Technologies and Noninvasive Circulating Biomarkers

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(14), P. 7548 - 7548

Published: July 7, 2022

The endothelium has multiple functions, ranging from maintaining vascular homeostasis and providing nutrition oxygen to tissues evocating inflammation under adverse conditions determining endothelial barrier disruption, resulting in dysfunction. Endothelial dysfunction represents a common condition associated with the pathogenesis of all diseases cardiovascular system, as well other systems human body, including sepsis, acute respiratory distress syndrome, COVID-19 distress. Such evidence is leading identification potential biomarkers therapeutic targets for preserving, reverting, or restoring integrity functionality by promptly treating its Here, some strategies achieving these goals are explored, despite diverse challenges that exist, necessitating significant bench work an increased number clinical studies.

Language: Английский

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Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Frontiers in Neurology, Journal Year: 2022, Volume and Issue: 13

Published: April 4, 2022

The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- motion-induced stimuli into electrical signals conveyed to brain. During evolution ear, major changes occurred in organ, whereas structure vestibular organs remained constant all vertebrates over same period. Vestibular deficits highly prevalent humans, due multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections aging. Studies deafness genes associated with balance their corresponding animal models have shed light development function these two sensory systems. Bilateral often impair individual postural control, gaze stabilization, locomotion spatial orientation. resulting dizziness, vertigo, and/or falls (frequent elderly populations) greatly affect patient quality life. In absence treatment, prosthetic devices, such as implants, providing information about direction, amplitude velocity body movements, being developed given promising results humans. Novel methods techniques led progress gene therapies targeting (gene supplementation editing), 3D organoids reprograming protocols generating cell-like cells. rapid advances multiscale approaches covering basic research, clinical diagnostics fostering interdisciplinary research develop personalized treatments disorders.

Language: Английский

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Gene therapy in pediatrics – Clinical studies and approved drugs (as of 2023)

Life Sciences, Journal Year: 2024, Volume and Issue: 348, P. 122685 - 122685

Published: May 6, 2024

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating range of genetic disorders that manifest childhood. involves the modification or correction mutated gene introduction functional into patient's cells. In general, it is implemented through two main modalities namely ex vivo and therapy. Currently, noteworthy array products has received valid market authorization, with several others various stages approval process. Additionally, multitude clinical trials are actively underway, underscoring dynamic progress within this field. Pediatric fields hematology, oncology, vision hearing loss, immunodeficiencies, neurological, metabolic areas interventions. This review provides comprehensive overview evolution current therapy-based treatments clinic pediatric patients. It navigates historical milestones therapies, currently approved by U.S. Food Drug Administration (FDA) and/or European Medicines Agency (EMA) children, promising future disorders. By providing thorough compilation drugs published results completed ongoing trials, serves as guide clinicians to get quick situation studies 2023.

Language: Английский

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The Opportunities and Challenges of Gene Therapy for Treatment of Inherited Forms of Vision and Hearing Loss

Human Gene Therapy, Journal Year: 2023, Volume and Issue: 34(17-18), P. 808 - 820

Published: Aug. 29, 2023

Inherited forms of blindness and deafness are highly prevalent severe conditions that significantly impact the lives millions people worldwide. The lack therapeutic options for these poses a major socioeconomic burden. Over last decades, gene therapy has proven to be life changing treatment hereditary acquired diseases, extensive preclinical investigation in animal models both retinal inner ear disorders highlighted promising translational opportunities too. This led dozens clinical trials investigating efficiency therapy-based approaches, with some products successfully reaching phase III development or even market authorization. However, challenges remain use therapy, which related features delivery vehicles currently available characteristics targeted. Therefore, further developments platforms' design, including exploitation novel technologies such as genome editing, RNA-targeted therapies, optogenetics, actively ongoing, driving field forward. In this study, we review ongoing applications achievements inherited well being pursued overcome current limitations.

Language: Английский

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Advancing precision ear medicine: leveraging animal models for disease insights and therapeutic innovations

Mammalian Genome, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Gene therapy offers significant promise for treating inner ear disorders, but its clinical translation requires robust preclinical validation, often reliant on animal models. This review examines the role of these models in advancing gene therapeutics inherited focusing successes, challenges, and treatment solutions. By providing a precise understanding disease mechanisms, offer versatile platform that is essential assessing validating therapies. Successful supplementation editing have shown potential restoring hearing balance functions preventing their decline. However, challenges such as limitations delivery methods, surgical access, immune responses, discrepancies manifestation between humans hinder translation. Current efforts are dedicated to developing innovative strategies aimed at enhancing efficiency delivery, overcoming physical barriers blood-labyrinth barrier, improving target specificity, maximizing therapeutic efficacy while minimizing adverse responses. Diverse strategies, along with evolving technologies, hold outcomes using relevant The future will hinge personalized therapies team science fueling interdisciplinary collaborations among researchers, clinicians, companies, regulatory agencies expedite from bench bedside unlock immense precision medicine ear.

Language: Английский

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Zebrafish cdh23 Affects Rod Cell Phototransduction Through Regulating Ca2+ Transport and MAPK Signaling Pathway

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4604 - 4604

Published: May 11, 2025

Mutations in the pathogenic gene CDH23 are known to cause Usher syndrome, affecting both auditory and visual functions. Our previous results provided valuable insights into mechanisms underlying congenital hearing loss associated with mutations. However, molecular signaling pathways that influence vision remain largely unknown. In this study, transcriptional sequencing bioinformatics analysis were conducted compare expression between control cdh23−/−. Additionally, RT-qPCR experiments performed further validate results. The comparative transcriptomic identified differentially expressed genes photoreceptor degeneration mitogen-activated protein kinase (MAPK) pathway. Embryos subjected hematoxylin eosin (H&E) staining assess their histological changes. showed cdh23−/− retina was morphologically indistinguishable from control. Apoptosis assessed using TUNEL staining, which revealed an increase total cell death retina. induced by Ca2+ MAPK interactions following degeneration. This study provides role of cdh23 vision.

Language: Английский

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The Genomics of Auditory Function and Disease

Annual Review of Genomics and Human Genetics, Journal Year: 2022, Volume and Issue: 23(1), P. 275 - 299

Published: June 6, 2022

Current estimates suggest that nearly half a billion people worldwide are affected by hearing loss. Because of the major psychological, social, economic, and health ramifications, considerable efforts have been invested in identifying genes molecular pathways involved loss, whether genetic or environmental, to promote prevention, improve rehabilitation, develop therapeutics. Genomic sequencing technologies led discovery associated with Studies transcriptome epigenome inner ear characterized key regulators development paved way for their use regenerative medicine. In parallel, immense preclinical success using viral vectors gene delivery animal models loss has motivated industry work on translating such approaches into clinic. Here, we review recent advances genomics auditory function dysfunction, from patient diagnostics epigenetics therapy.

Language: Английский

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Poly(β-amino ester) Nanoparticles Modified with a Rabies-Virus-Derived Peptide for the Delivery of ASCL1 across a 3D In Vitro Model of the Blood–Brain Barrier

ACS Applied Nano Materials, Journal Year: 2023, Volume and Issue: 6(7), P. 6299 - 6311

Published: March 31, 2023

Gene editing has emerged as a therapeutic approach to manipulate the genome for killing cancer cells, protecting healthy tissues, and improving immune response tumor. The gene tool achaete-scute family bHLH transcription factor 1 CRISPR guide RNA (ASCL1-gRNA) is known restore neuronal lineage potential, promote terminal differentiation, attenuate tumorigenicity in glioblastoma tumors. Here, we fabricated polymeric nonviral carrier encapsulate ASCL1-gRNA by electrostatic interactions deliver it into cells across 3D vitro model of blood–brain barrier (BBB). To mimic rabies virus (RV) neurotropism, gene-loaded poly(β-amino ester) nanoparticles are surface functionalized with peptide derivative glycoprotein (RVG29). capability obtained NPs, hereinafter referred RV-like travel BBB, internalize investigated BBB through flow cytometry CLSM microscopy. formation nicotinic acetylcholine receptors confirmed immunochemistry. These bind RVG29. Unlike Lipofectamine which primarily internalizes transfects endothelial NPs capable model, preferentially internalizing delivering at an efficiency 10%, causing noncytotoxic effects.

Language: Английский

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