Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa

Li, Sujun; Datta, Shyamtanu; Brabbit, Emily; Love, Zoe; Woytowicz, Victoria; Flattery, Kyle; Capri, Jessica; Yao, Katie; Wu, Siqi; Imboden, Michael; Upadhyay, Ajay Kumar; Arumugham, Rasappa; Thoreson, Wallace B.; DeAngelis, Margaret M.; Haider, Neena B.

doi:10.1038/s41434-020-0134-z

Cited by 43 publications

(63 citation statements)

References 103 publications

(119 reference statements)

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“…There are many factors can influence the range of phenotypes seen in a disease including; epigenetic factors, environment, allelic heterogeneity and genetic modifiers [45,49,50]. The presence of as yet unidentified polymorphisms in other genes known to interact with NR2E3 such as NRL, CRX, NEUROD1, RORA and TRβ2 may also be influencing the phenotypic outcome [26].…”

Section: Discussionmentioning

confidence: 99%

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Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Al‐Khuzaei

Broadgate

Halford

et al. 2020

Genes

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A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent study of a mouse model has shown that delivery of NR2E3 to retinal cells stabilises disease progression [50]. With potential treatment prospects in the pipeline, obtaining a genetic diagnosis and characterising the phenotype in depth is of increasing importance.…”

Section: Discussionmentioning

confidence: 99%

Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Al‐Khuzaei

Broadgate

Halford

et al. 2020

Genes

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“…Naessens et al provided proof-of-concept of an antisense oligonucleotide capable of NE2E3 knockdown in vitro but did not investigate functional consequences [80]. Interestingly, a report using a gene therapy NR2E3 overexpression strategy also showed promise in mouse retinal degeneration models [81]. Wild-type NR2E3 cDNA was packaged into an AAV8 vector and injected subretinally in various mouse retinal degeneration models; AAV8-Nr2e3 treatment at P0 preserved ONL photoreceptor density, increased green and blue opsin + and rhodopsin + cells, and improved ERG response, which the authors attributed to increased recruitment of phototransduction-relevant transcription factors in a number of rodent preclinical models of RP [81].…”

Section: Manipulating the Nr2e3 Pathway As A Neuroprotective Strategymentioning

confidence: 99%

“…Interestingly, a report using a gene therapy NR2E3 overexpression strategy also showed promise in mouse retinal degeneration models [81]. Wild-type NR2E3 cDNA was packaged into an AAV8 vector and injected subretinally in various mouse retinal degeneration models; AAV8-Nr2e3 treatment at P0 preserved ONL photoreceptor density, increased green and blue opsin + and rhodopsin + cells, and improved ERG response, which the authors attributed to increased recruitment of phototransduction-relevant transcription factors in a number of rodent preclinical models of RP [81]. This suggests that modulation of the NR2E3 pathway (either inhibition or upregulation) in mouse models of RP may therefore slow retinal degeneration by either similar or distinct mechanisms.…”

Section: Manipulating the Nr2e3 Pathway As A Neuroprotective Strategymentioning

confidence: 99%

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Moore

Skowronska‐Krawczyk

Chao³

2020

JCM

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Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper ( NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

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“…Recent studies propose Nr2e3 as a genetic modifier and broad-spectrum therapeutic agent to treat multiple forms of RP (Li et al, 2020) (Project Marató 201417-30-31-32); and the Instituto de Salud Carlos III, cofounded with the European Regional Development Fund (ERDF) within the "Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020" (RD16/0008/0020; FIS/PI 18-00754) to PdlV. IAM is a fellow of the APIF-2019 (Universitat de Barcelona).…”

mentioning

confidence: 99%

Nr2e3 functional domain ablation by CRISPR-Cas9D10A identifies a new isoform and generates Retinitis Pigmentosa and Enhanced S-cone Syndrome models

Aísa-Marín

Lopez-Iniesta

Milla

et al. 2020

Preprint

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Mutations in NR2E3 cause retinitis pigmentosa (RP) and enhanced S-cone syndrome (ESCS) in humans. This gene produces a large isoform encoded in 8 exons and a previously unreported shorter isoform of 7 exons, whose function is unknown. We generated two mouse models by targeting exon 8 of Nr2e3 using CRISPR/Cas9-D10A nickase. Allele D27 is an in-frame deletion of 27 bp that ablates the dimerization domain, whereas allele DE8 (full deletion of exon 8), produces only the short isoform that lacks the dimerization and repressor domains. The D27 mutant shows developmental alterations and a non-progressive electrophysiological dysfunction that resembles the ESCS phenotype. The DE8 mutant exhibits progressive retinal degeneration, as occurs in human RP patients. Interestingly, the mutant retinas show invaginations similar to fovea-like pits. Our mutants suggest a role of Nr2e3 as a conepatterning regulator and provide valuable models for studying mechanisms of NR2E3associated retinal dystrophies and evaluating potential therapies.

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Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa

Cited by 43 publications

References 103 publications

Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Nr2e3 functional domain ablation by CRISPR-Cas9D10A identifies a new isoform and generates Retinitis Pigmentosa and Enhanced S-cone Syndrome models

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