ArticleHuman gene therapy2015
Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1.
Article in Human gene therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Streamlined synthetic regulatory cassette for efficient and photoreceptor-enriched retinal gene expression.Molecular therapy. Nucleic acids · 2026Article
- Gene therapy rescues cone function inMolecular therapy. Advances · 2026Article
- Gene therapy rescues cone function in an all-cone retina mouse model with the most common cone opsin C203R missense mutation.PloS one · 2026Article
- Current clinical applications of AAV-mediated gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Vulnerability of the NrlAdvances in experimental medicine and biology · 2025Article
- Development of an AAV-CRISPR-Cas9-based treatment for dominant cone-rod dystrophy 6.Molecular therapy. Methods & clinical development · 2023Article
- Preclinical studies in support of phase I/II clinical trials to treatMolecular therapy. Methods & clinical development · 2023Article
- Effective gene therapy of Stargardt disease with PEG-ECO/Molecular therapy. Nucleic acids · 2022Article
- Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials.The British journal of ophthalmology · 2022Review
- Preventing Neurodegeneration by Controlling Oxidative Stress: The Role of OXR1.Frontiers in neuroscience · 2020Review
- CRISPR Activation EnhancesMolecular therapy. Methods & clinical development · 2019Article
- Somatic Gene Editing ofHuman gene therapy · 2019Article
- Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision.Investigative ophthalmology & visual science · 2019Article
- Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors.Progress in retinal and eye research · 2018Review
- The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx.The Journal of biological chemistry · 2018Article
- Gene therapy and genome surgery in the retina.The Journal of clinical investigation · 2018Review
- Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors.The Journal of biological chemistry · 2018Article
- GUCY2D Cone-Rod Dystrophy-6 Is a "Phototransduction Disease" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Gene-methylation epistatic analyses via the W-test identifies enriched signals of neuronal genes in patients undergoing lipid-control treatment.BMC proceedings · 2018Article
- Rod Outer Segment Development Influences AAV-Mediated Photoreceptor Transduction After Subretinal Injection.Human gene therapy · 2017Article
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in GUCY2D are the cause of Leber congenital amaurosis type 1 (LCA1). GUCY2D encodes retinal guanylate cyclase-1 (retGC1), a protein expressed exclusively in outer segments of photoreceptors and essential for timely recovery from photoexcitation. Recent clinical data show that, despite a high degree of visual disturbance stemming from a loss of cone function, LCA1 patients retain normal photoreceptor architecture, except for foveal cone outer segment abnormalities and, in some patients, foveal cone loss. These results point to the cone-rich central retina as a target for GUCY2D replacement. LCA1 gene replacement studies thus far have been conducted in rod-dominant models (mouse) or with vectors and organisms lacking clinical translatability. Here we investigate gene replacement in the Nrl(-/-) Gucy2e(-/-) mouse, an all-cone model deficient in retGC1. We show that AAV-retGC1 treatment fully restores cone function, cone-mediated visual behavior, and guanylate cyclase activity, and preserves cones in treated Nrl(-/-) Gucy2e(-/-) mice over the long-term. A novel finding was that retinal function could be restored to levels above that in Nrl(-/-) controls, contrasting results in other models of retGC1 deficiency. We attribute this to increased cyclase activity in treated Nrl(-/-) Gucy2e(-/-) mice relative to Nrl(-/-) controls. Thus, Nrl(-/-) Gucy2e(-/-) mice possess an expanded dynamic range in ERG response to gene replacement relative to other models. Lastly, we show that a candidate clinical vector, AAV5-GRK1-GUCY2D, when delivered to adult Nrl(-/-) Gucy2e(-/-) mice, restores retinal function that persists for at least 6 months. Our results provide strong support for clinical application of a gene therapy targeted to the cone-rich, central retina of LCA1 patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.