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Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

ABSTRACT: Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.

SUBMITTER: Petersen-Jones SM

PROVIDER: S-EPMC5749539 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

Petersen-Jones Simon M SM Occelli Laurence M LM Winkler Paige A PA Lee Winston W Sparrow Janet R JR Tsukikawa Mai M Boye Sanford L SL Chiodo Vince V Capasso Jenina E JE Becirovic Elvir E Schön Christian C Seeliger Mathias W MW Levin Alex V AV Michalakis Stylianos S Hauswirth William W WW Tsang Stephen H SH

The Journal of clinical investigation 20171120 1

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of pro ...[more]

PMID: 29202463

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Project description:BackgroundRetinal dystrophies constitute a group of diseases characterized by clinical variability and pronounced genetic heterogeneity. Retinitis pigmentosa is the most common subtype of hereditary retinal dystrophy and is characterized by a progressive loss of peripheral field vision (Tunnel Vision), eventual loss of central vision, and progressive night blindness. The characteristics of the fundus changes include bone-spicule formations, attenuated blood vessels, reduced and/or abnormal electroretinograms, changes in structure imaged by optical coherence tomography, and subjective changes in visual function. The different syndromic and nonsyndromic forms of retinal dystrophies can be attributed to mutations in more than 250 genes. Molecular diagnosis for patients with retinitis pigmentosa has been hampered by extreme genetic and clinical heterogeneity between retinitis pigmentosa and other forms of retinal dystrophies. Next generation sequencing (NGS) technologies are among the most promising techniques to identify pathogenic variations in retinal dystrophies.PurposeThe purpose of this study was to discover the molecular diagnosis for Brazilian patients clinically diagnosed with a retinitis pigmentosa pattern of inheritance by using NGS technologies.Materials and methodsSixteen patients with the clinical diagnosis of retinitis pigmentosa were included in the study. Their DNA was sequenced in a panel with 132 genes related to retinal dystrophies using the Illumina® platform. Sequence analysis and variation calling was performed using Soft Genetics®, NextGene, and Geneticist Assistant software. The criteria for pathogenicity analysis were established according to the results of prediction programs (Polyphen 2, Mutation taster and MetaCore™) and comparison of pathogenic variations found with databases.ResultsThe identified potentially pathogenic variations were all confirmed by Sanger sequencing. There were 89 variations predicted as pathogenic, but only 10 of them supported the conclusion of the molecular diagnosis. Five of the nine patients were autosomal dominant RP (56%), two (22%) were autosomal recessive RP, and two (22%) were X-linked RP. Nine of the 16 patients (56%) had probably positive or positive results.ConclusionThe Next Generation Sequencing used in this study allowed the molecular diagnosis to be confirmed in 56% of the patients and clarified the inheritance pattern of the patient's retinal dystrophies.

Dataset Information

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

Publications

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach.

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