Clinical Characterization of Retinitis Pigmentosa Associated With Variants in <i>SNRNP200</i>

Yusuf, Imran H.; Birtel, Johannes; Shanks, Morag; Clouston, Penny; Downes, Susan M.; Issa, Peter Charbel; MacLaren, Robert E.

doi:10.1001/jamaophthalmol.2019.3298

Cited by 10 publications

(2 citation statements)

References 12 publications

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“…One of the main aspect of a trial for RP treatment is to recruit a population of patients with a homogenous secondary degeneration of cones [41,[177][178][179][180][181][182][183][184]. While the protection of cone function using RdCVF and RdCVFL is predicted to be independent of the causative mutation, in a first stage of a clinical trial recruiting a RP cohort representing a full diversity of mutation in the 65 causative genes reported so far (https://sph.uth.edu/retnet/) may result in an enormous phenotype heterogeneity that will mask any possible benefit for vision after statistical analysis.…”

Section: Clinical Trialmentioning

confidence: 99%

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Clérin

Marussig

Sahel

et al. 2020

IJMS

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The loss of cone photoreceptor function in retinitis pigmentosa (RP) severely impacts the central and daily vision and quality of life of patients affected by this disease. The loss of cones follows the degeneration of rods, in a manner independent of the causing mutations in numerous genes associated with RP. We have explored this phenomenon and proposed that the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF) encoded by the nucleoredoxin-like 1 (NXNL1) gene which interrupts the metabolic and redox signaling between rods and cones. After providing scientific evidence supporting this mechanism, we propose a way to restore this lost signaling and prevent the cone vision loss in animal models of RP. We also explain how we could restore this signaling to prevent cone vision loss in animal models of the disease and how we plan to apply this therapeutic strategy by the administration of both products of NXNL1 encoding the trophic factor RdCVF and the thioredoxin enzyme RdCVFL using an adeno-associated viral vector. We describe in detail all the steps of this translational program, from the design of the drug, its production, biological validation, and analytical and preclinical qualification required for a future clinical trial that would, if successful, provide a treatment for this incurable disease.

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Section: Clinical Trialmentioning

confidence: 99%

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Clérin

Marussig

Sahel

et al. 2020

IJMS

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“…The development of high-throughput DNA sequencing methods has made it more feasible to also achieve diagnoses on a molecular level. Targeted Next-Generation Sequencing (NGS) in particular has been proven as an efficient tool and allows IRD differentiation according to their genetic causes in daily practice [4][5][6][7][8][9][10][11][12][13][14][15][16]. One strength of NGS is that a large variety of genes associated with IRDs can be studied simultaneously at relatively low cost.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Birtel

Gliem

Hess

et al. 2020

Genes

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Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.

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Retinitis Pigmentosa

2022

Inherited Retinal Disease

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Clinical Characterization of Retinitis Pigmentosa Associated With Variants in SNRNP200

Cited by 10 publications

References 12 publications

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Retinitis Pigmentosa

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