A Comprehensive Review of Clinically Applied Adeno-Associated Virus-Based Gene Therapies for Ocular Disease

Human Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

The eye is an ideal target for gene therapy due its accessibility, immune privilege, small size, and compartmentalization. Adeno-associated virus (AAV) the gold standard vector delivery can be injected via multiple routes of administration to different parts this organ. approval Luxturna™, a subretinally delivered RPE65-associated Leber's congenital amaurosis, large number successful proof concept studies performed in animal models great momentum into pursuit additional AAV-based therapies treatment retinal disease. This review provides comprehensive summary all subretinally, intravitreally, suprachoroidally ocular that have progressed clinical stage. Attention given primary (safety) secondary (efficacy) outcomes, or lack thereof. Lessons learned future directions are addressed, both which point optimism field poised continued regulatory approvals.

Language: Английский

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PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, progressive blindness form retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding single AAV packaging limit employing a dual adeno-associated virus (AAV) strategy to deliver full-length PCDH15 coding sequence. We demonstrate efficacy mouse models, effectively restoring balance these mice. Importantly, our also proves successful expressing protein clinically relevant retinal including human organoids non-human primate retina, showing efficient targeting photoreceptors proper expression calyceal processes. This research represents major step toward advancing therapy multiple challenges hearing, vision impairment.

Language: Английский

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Research hotspots and trends of the <i>SLC26A4</i> gene-related hearing loss from the perspective of knowledge graph

Intractable & Rare Diseases Research, Journal Year: 2025, Volume and Issue: 14(1), P. 55 - 66

Published: Jan. 31, 2025

This article aims to identify research hotspots and trends in on SLC26A4 gene-related hearing loss through bibliometric visual analyses, providing a reference direction for future research. Publications gene from 1994 2023 were retrieved the Web of Science Core Collection database. Bibliometric analysis was conducted using Bibliometrix 4.0.0 R package, CiteSpace 6.2.R6 software, VOSviewer 1.6.20. The encompassed journals, authors, keywords, institutions, countries, references. Based results, network maps generated evaluate collaborations among keyword co-occurrences, co-citation study identified 1,308 publications 62 countries. Annual publication numbers have increased with fluctuations, showing rapid growth since 2011. USA emerged as leading contributor this field based scientific production, citations, cooperation networks. International Journal Pediatric Otorhinolaryngology had highest number publications, while Laryngoscope most cited journal. Harvard University productive institution. Key researchers included Dai Pu, Griffith Andrew J., Usami Shin-Ichi. There been active between institutions. primary topics focused genotype-phenotype correlations, genetic screening, diagnostic advancements, exploration pathogenic mechanisms. Research has notably 2011, ongoing clinical investigations basic efforts. Future studies may further explore disease mechanisms potential therapeutic interventions related gene.

Language: Английский

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Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models

Science Advances, Journal Year: 2025, Volume and Issue: 11(13)

Published: March 26, 2025

Retinal gene therapy using dual adeno-associated viral (AAV) intein vectors can be applied to genetic forms of blindness caused by mutations in genes with coding sequences that exceed single AAV cargo capacity, such as Stargardt disease (STGD1), the most common inherited macular dystrophy. In view clinical translation vectors, here we set evaluate both efficiency and safety their subretinal administration relevant large animal models. Accordingly, have developed first pig model STGD1, which found accumulate lipofuscin similarly patients. This accumulation is significantly reduced upon whose pharmacodynamics then tested nonhuman primates, showed modest reversible inflammation well high levels photoreceptor transduction. bodes for further patients STGD1 other blinding diseases require delivery genes.

Language: Английский

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Non-viral gene therapy for Leber’s congenital amaurosis: progress and possibilities

Nanomedicine, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 14

Published: Dec. 20, 2024

Leber's congenital amaurosis (LCA) represents a set of rare and pervasive hereditary conditions the retina that cause severe vision loss starting in early childhood. Targeted treatment intervention has become possible thanks to recent advances understanding LCA genetic basis. While viral vectors have shown efficacy gene delivery, they present challenges related safety, low cargo capacity, potential for random genomic integration. Non-viral therapy is safer more flexible alternative treating underlying mutation causing LCA. delivery methods, such as inorganic nanoparticles, polymer-based systems, lipid-based bypass risks immunogenicity integration, potentially offering versatile personalized patients. This review explores background LCA, emphasizing mutations involved, diverse non-viral methods being developed. It also highlights studies on animal models clinical trials. presents future perspectives therapy, including integrating emerging technologies like CRISPR-Cas9, interdisciplinary collaborations, medicine, ethical considerations.

Language: Английский

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Gene therapy proves successful in treating hereditary deafness

The Lancet, Journal Year: 2024, Volume and Issue: 403(10441), P. 2267 - 2269

Published: May 1, 2024

Language: Английский

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PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 13, 2023

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, progressive blindness form retinitis pigmentosa. In this study, we explore a novel approach for USH1F gene therapy, exceeding single AAV packaging limit employing dual adeno-associated virus (AAV) strategy to deliver full-length PCDH15 coding sequence. We demonstrate efficacy mouse models, effectively restoring balance these mice. Importantly, our also proves successful expressing clinically relevant retinal including human organoids non-human primate retina, showing efficient targeting photoreceptors proper protein expression calyceal processes. This research represents major step toward advancing therapy multiple challenges hearing, vision impairment.

Language: Английский

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The single-cell transcriptomic landscape of the topological differences in mammalian auditory receptors

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(11), P. 2398 - 2410

Published: July 29, 2024

Language: Английский

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A patient with 18p11.32-p11.21 deletion have monaural deafness caused by an inadequate haplodose of THOC1: A case report

Medicine, Journal Year: 2024, Volume and Issue: 103(30), P. e39048 - e39048

Published: July 26, 2024

Background: THOC1 mutation causes Deafness, autosomal dominant 86 [OMIM: 620280]. However, it has not been reported whether deletion of the gene deafness. Methods: Here, we report a 1-year-old girl with clinical features including Hypotonia, unilateral deafness in right ear, and widening lateral ventricles 6 months. Gene mutations were identified by whole-exome sequencing. Results: Through sequencing, 18p11.32-p11.21 contains all genes found patient but her parents’ genomic DNA. The ClinGen Database Haplodose Insufficiency (HI) prediction tool determined that HI, HI may cause Moreover, after months rehabilitation training, muscle tone returned to normal. at age 1 year, developed symptoms large liver hamartoma both kidneys. Conclusion: From above results, propose our patient, Therefore, this study provides new associated

Language: Английский

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Review research designed to investigate gene function and possible impact of specific variants

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 315 - 353

Published: Nov. 1, 2024

Language: Английский

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