Exploiting metabolic and antioxidant pathways to maintain vision in blinding disease

Ramachandran, Pavitra S.; Song, Ji Yun; Bennett, Jean

doi:10.1172/jci80821

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…Generic, antioxidant gene therapies such as NFE2L2 overexpression would be much cheaper and easier to implement than gene-specific augmentation therapies. 66 …”

Section: Main Textmentioning

confidence: 99%

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Coppieters

Ascari

Dannhausen

et al. 2016

The American Journal of Human Genetics

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Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.

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“…Generic, antioxidant gene therapies such as NFE2L2 overexpression would be much cheaper and easier to implement than gene-specific augmentation therapies. 66 …”

Section: Main Textmentioning

confidence: 99%

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Coppieters

Ascari

Dannhausen

et al. 2016

The American Journal of Human Genetics

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“…The greater loss of sensitivity for S-cones than L-and M-cones in the absence of functional rods may be likely explained by a combination of multiple mechanisms leading to metabolic damage that have been previously studied in animal models of RP (e.g., structural, toxic, nutritional, trophic, and/or oxidative factors) [21][22][23]. While it is not currently possible to measure these factors in the retina of human subjects, future clinical trials of therapeutic interventions (e.g., involving neurotrophic or oxidative factors) may be valuable to help explore whether such treatment approaches might impact the function of individual photoreceptor types in people with RP, as well as the possible relationship with these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Reliability of Mesopic Measures of Visual Acuity and Contrast Sensitivity and Their Correlation with Rod and Cone Function in Retinitis Pigmentosa

Bittner

Ferraz

2019

Ophthalmic Res

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Background: Mesopic conditions elicit both rod and cone responses, and they are more commonly encountered in daily life than are scotopic conditions; yet visual function outcome measures of mesopic visual acuity (VA) or contrast sensitivity (CS) are rarely evaluated. Objective: In retinitis pigmentosa (RP), we explored whether visual reductions in mesopic versus photopic conditions were correlated with cone or rod function, as well as the between-visit test-retest variability in mesopic measures. Methods: At each of two visits, 22 RP subjects completed mesopic and photopic ETDRS VA and Pelli-Robson chart CS tests obtained with and without a U23 NoIR 4% transmission filter; testing of perifoveal scotopic cone or rod sensitivity with the AdaptDx; and the Rabin Cone Contrast Test (CCT). Results: A greater CS reduction in mesopic versus photopic conditions was significantly related to absence of scotopic rod function (p = 0.038) or longer self-reported duration of night vision loss (p = 0.044). VA reductions > 0.2 logMAR in mesopic versus photopic conditions were significantly related to reduced cone-mediated scotopic sensitivity (p = 0.038). Significant predictors of the CCT ratio of Scone to M-and L-cone sensitivity were mesopic VA (p = 0.038) and absence of AdaptDx rod function (p = 0.008). Test-retest 95% coefficients of repeatability were not significantly different when comparing between photopic and mesopic tests of VA (0.16 and 0.12 logMAR, respectively) or CS (0.21 and 0.24 logCS, respectively). Conclusions: Perifoveal scotopic rod and cone function measured with the AdaptDx was significantly correlated with mesopic CS and VA, respectively, which had good, acceptable test-retest repeatability; thus, they appear to be suitable outcome measures to monitor mesopic visual function in clinical practice or trials. RP subjects with reduced mesopic VA and no perifoveal rod function had a greater loss of sensitivity for Scones than for L-/M-cones.

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“…Afterwards the complete loss of the cone soma and pedicle occurs in part of the patients (4). Preserving the remaining high-acuity central vision in patients has been a major goal of recent gene therapy studies (5)(6)(7)(8)(9). Indeed, the rst successful clinical trials of gene therapy have focused on gene addition, where a wildtype cDNA copy is brought by a vector to supplement the defective gene.…”

Section: Introductionmentioning

confidence: 99%

Reactivating the phototransduction cascade by universally applicable gene therapy preserves retinal function in Rod-Cone dystrophy

Simon

Khabou

Finzi

et al. 2022

Preprint

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Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a group of inherited disorders characterized by rod degeneration followed by degeneration of peripheral cones, leaving patients with tunnel vision in mid stages and blindness in the latest stages. Previous studies expressed microbial chloride pumps, in degenerating cone photoreceptors to restore these cells’ activity and prolong vision. Microbial opsins lack intracellular signal amplification, requiring high light intensities. To develop a more sensitive strategy; we examined the phototransduction cascade in degenerating cones, in two RCD mouse models. We found that opsin and arrestin expression is maintained in the soma during outer segment degeneration. We thus hypothesized that cone reactivation based on cone opsin signaling may be feasible by expressing a target channel activated by G proteins recruited by cone opsin. Adeno-associated viral (AAV) mediated expression of G protein coupled inwardly rectifying K (GIRK) channel provided improvements in visual function in two RCD mouse models with mutations in two distinct genes. Importantly, we confirmed cone opsin and cone arrestin expression in cones of late-stage RCD patients, validating the rationale of GIRK-mediated gene therapy in humans. We propose GIRK channel expression in cones as a new approach to maintain high acuity, high sensitivity, color vision in RCD independently of the underlying mutation.

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Exploiting metabolic and antioxidant pathways to maintain vision in blinding disease

Abstract: C o m m e n t a r y 1 3 9 0

Cited by 5 publications

References 21 publications

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Reliability of Mesopic Measures of Visual Acuity and Contrast Sensitivity and Their Correlation with Rod and Cone Function in Retinitis Pigmentosa

Reactivating the phototransduction cascade by universally applicable gene therapy preserves retinal function in Rod-Cone dystrophy

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