<i>Nrl</i>-Knockout Mice Deficient in Rpe65 Fail to Synthesize 11-<i>cis</i>Retinal and Cone Outer Segments

Feathers, Kecia L.; Lyubarsky, Arkady; Khan, Naheed W.; Teofilo, Karen; Swaroop, Anand; Williams, David S.; Pugh, Edward N.; Thompson, Debra A.

doi:10.1167/iovs.07-1234

Cited by 42 publications

(50 citation statements)

References 40 publications

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“…The role(s) played by RPE65 in providing chromophore for cone function and/or survival remains unclear and controversial (1,3,40,(43)(44)(45)(46)(47)(48)(49). Restoration of cone-as well as rod photoreceptor-based visual function by subretinal AAV gene therapy in the canine model of RPE65-LCA (4,8), together with the existence of remnant cone function in patients with untreated RPE65-LCA (3), suggested a potential to improve cone function in patients undergoing gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

Cideciyan

Alemán

Boye

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

608

515

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The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone-and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod-and cone-photoreceptor-based vision after RPE65 gene therapy. dark adaptation ͉ photoreceptor ͉ retinal degeneration ͉ retinoid cycle T he enzymatic pathway in the human eye that regenerates light-altered vitamin A molecules is known as the retinoid cycle of vision. Molecular defects in retinoid cycle genes can lead to inherited retinal diseases in man (1). The severity of visual disturbance in these diseases is thought to be related to how the mutation alters the biochemical activity and whether there is redundancy at the multiple biochemical steps of the cycle. A severe form of incurable childhood blindness, Leber congenital amaurosis (LCA), is caused by mutations in RPE65 (retinal pigment epithelium-specific protein, 65 kDa), the gene in the retinal pigment epithelium (RPE) that encodes the isomerase. This is the only known enzyme that catalyzes isomerization of all-trans-retinyl esters to 11-cis-vitamin A. In RPE65 deficiency, photoreceptor cells do not regenerate their visual pigment and vision is not sustained. Retinal anatomy also degenerates, but not entirely (2, 3).RPE65-deficient animals have been characterized, and proofof-principle studies using recombinant adeno-associated virus (AAV) vector delivery of RPE65 to RPE cells have described restoration of vision (2,(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These studies provided the impetus for human safety studies of RPE65 gene replacement (trials NCT00481546, NCT00643747, NCT00516477, and NCT00422721, www.clinicaltri...

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Section: Discussionmentioning

confidence: 99%

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

Cideciyan

Alemán

Boye

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

608

515

View full text Add to dashboard Cite

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“…Whereas the majority of researchers have found that in the RPE65 knock-out mouse, both rod and cone photoreceptors were severely impaired (Fan et al, 2003;Feathers et al, 2008;Seeliger et al, 2001;Wenzel et al, 2007), Redmond et al had shown that although rod-driven ERG responses were abolished, cone function still remained intact. This finding led them to speculate that cones might use a different pathway for regenerating their pigment.…”

Section: Vision In Canonical Cycle-deficient Zebrafishmentioning

confidence: 99%

“…Thus, cone photoreceptors were thought to rely entirely on the canonical visual cycle for chromophore regeneration (Fan et al, 2003;Feathers et al, 2008;Seeliger et al, 2001;Wenzel et al, 2007). This hypothesis has been challenged by the recent findings of Wang and Kefalov, who provided clear evidence for an intra-retinal visual cycle in the rod-dominant mouse and salamander, which will be discussed in more detail below .…”

Section: Alternative Cone Visual Cycle In Cone-dominant Speciesmentioning

confidence: 99%

“…However due to conflicting data in different studies, the question if an intra-retinal visual cycle exists in rod-dominant species remained controversial until recently (Fan et al, 2003;Feathers et al, 2008;Redmond et al, 2005;Redmond et al, 1998;Seeliger et al, 2001;Wenzel et al, 2007).…”

Section: Vision In Canonical Cycle-deficient Zebrafishmentioning

confidence: 99%

“…Until very recently it was claimed by the majority of researchers working with rodent models that rod-dominant species entirely rely on the canonical visual cycle for chromophore recycling (Fan et al, 2003;Feathers et al, 2008;Seeliger et al, 2001;Wenzel et al, 2007). The data arguing in favor of a second, cone-specific visual cycle, acquired in the cone-dominant models chicken, ground squirrel and zebrafish had been acknowledged, but it had been speculated that this discrepancy might be due to species differences.…”

Section: Cone Visual Cycle In Primatesmentioning

confidence: 99%

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Parallel visual cycles in the zebrafish retina

Fleisch

2010

Progress in Retinal and Eye Research

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Vertebrate vision necessitates continuous recycling of the chromophore 11-cis retinal (RAL). The classical (or canonical) visual cycle employs a number of enzymes located in the photoreceptor outer segment and RPE (retinal pigment epithelium) of the retina to regenerate 11-cis RAL from all-trans RAL. Cone-dominant species are believed to utilize a second, intra-retinal, pathway for 11-cis RAL generation, involving retinal Müller glia cells. This review summarizes the efforts made in zebrafish to gain a better understanding of the role of these two visual cycles for rod and cone photoreceptor chromophore recycling.

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Animal modelling for inherited central vision loss

Kostic

Arsenijévic

2015

The Journal of Pathology

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Disease‐causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale‐up of new therapies. Examples of innovative approaches will be presented such as lentiviral‐based transgenesis in pigs and adeno‐associated virus (AAV)‐gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Nrl-Knockout Mice Deficient in Rpe65 Fail to Synthesize 11-cisRetinal and Cone Outer Segments

Cited by 42 publications

References 40 publications

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

Parallel visual cycles in the zebrafish retina

Animal modelling for inherited central vision loss

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