ArticleHuman molecular genetics2011
Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed.
- Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Trial
- In vivo CRISPR gene editing in patients with herpetic stromal keratitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Trial
- Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect.Nature medicine · 2019Trial
- Revisiting retinal and macular degeneration in the genomics era.Nature reviews. Genetics · 2026Review
- Photoreceptor Disease at Ambiguous Transition Zones in Inherited Retinal Degenerations.Translational vision science & technology · 2025Article
- Retinal Degeneration Associated With Biallelic RDH12 Variants: Longitudinal Evaluation of Retinal Structure and Visual Function in Pediatric Patients.Investigative ophthalmology & visual science · 2024Article
- IQCB1 (NPHP5)-Retinopathy: Clinical and Genetic Characterization and Natural History.American journal of ophthalmology · 2024Article
- The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort.International journal of molecular sciences · 2024Article
- Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide inAmerican journal of ophthalmology case reports · 2023Article
- Mechanism of Cone Degeneration in Retinitis Pigmentosa.Cellular and molecular neurobiology · 2023Review
- Article
- New frontiers of retinal therapeutic intervention: a critical analysis of novel approaches.Annals of medicine · 2022Review
- Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.Investigative ophthalmology & visual science · 2022Article
- In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells.Stem cell reports · 2022Article
- Newer therapeutic options for inherited retinal diseases: Gene and cell replacement therapy.Indian journal of ophthalmology · 2022Review
- Restoration of Cone Sensitivity to Individuals with Congenital Photoreceptor Blindness within the Phase 1/2 Sepofarsen Trial.Ophthalmology science · 2022Article
- Natural history of retinal degeneration in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses.Scientific reports · 2022Article
- Case Report: Identification of likely recurrentF1000Research · 2022Article
- Super-resolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein CEP290.JCI insight · 2021Article
- Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors.
Funding
Abstract
Leber congenital amaurosis (LCA), a severe autosomal recessive childhood blindness, is caused by mutations in at least 15 genes. The most common molecular form is a ciliopathy due to NPHP6 (CEP290) mutations and subjects have profound loss of vision. A similarly severe phenotype occurs in the related ciliopathy NPHP5 (IQCB1)-LCA. Recent success of retinal gene therapy in one form of LCA prompted the question whether we know enough about human NPHP5 and NPHP6 disease to plan such treatment. We determined that there was early-onset rapid degeneration of rod photoreceptors in young subjects with these ciliopathies. Rod outer segment (OS) lamination, when detectable, was disorganized. Retinal pigment epithelium lipofuscin accumulation indicated that rods had existed in the past in most subjects. In contrast to early rod losses, the all-cone human fovea in NPHP5- and NPHP6-LCA of all ages retained cone nuclei, albeit with abnormal inner segments and OS. The rd16 mouse, carrying a hypomorphic Nphp6 allele, was a good model of the rod-dominant human extra-foveal retina. Rd16 mice showed normal genesis of photoreceptors, including the formation of cilia, followed by abnormal elaboration of OS and rapid degeneration. To produce a model of the all-cone human fovea in NPHP6-LCA, we generated rd16;Nrl-/- double-mutant mice. They showed substantially retained cone photoreceptors with disproportionate cone function loss, such as in the human disease. NPHP5- and NPHP6-LCA across a wide age spectrum are thus excellent candidates for cone-directed gene augmentation therapy, and the rd16;Nrl-/- mouse is an appropriate model for pre-clinical proof-of-concept studies.
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