Impairment of the Transient Pupillary Light Reflex in<i>Rpe65</i><sup>−/−</sup>Mice and Humans with Leber Congenital Amaurosis

Alemán, Tomás S.; Jacobson, Samuel G.; Chico, John D.; Scott, Michele L.; Cheung, Andy Y.; Windsor, Elizabeth A. M.; Furushima, Masatoshi; Redmond, T. Michael; Bennett, Jean; Palczewski, Krzysztof; Cideciyan, Artur V.

doi:10.1167/iovs.03-1230

Cited by 93 publications

(98 citation statements)

References 59 publications

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“…The data presented here suggest that the loss of RPE65, or its defects, may also be detrimental (at least partially) to the non-image-forming visual functions in these LCA patients. The rod-cone vision of rpe65 Ϫ/Ϫ mice can be rescued by exogenous 9-cis-retinal or 11-cis-retinal, suggesting a potential therapy for restoring vision in these LCA patients (18,24,25,36). The same may apply to the non-image-forming visual functions.…”

Section: Discussionmentioning

confidence: 93%

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Zhong

Wang

et al. 2005

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

133

108

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In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate non-image-forming visual functions such as pupillary light reflex (PLR) and circadian photoentrainment. This photosensitivity requires melanopsin, an invertebrate opsin-like protein expressed by the ipRGCs. The precise role of melanopsin remains uncertain. One suggestion has been that melanopsin may be a photoisomerase, serving to regenerate an unidentified pigment in ipRGCs. This possibility was echoed by a recent report that melanopsin is expressed also in the mouse retinal pigment epithelium (RPE), a key center for regeneration of rod and cone pigments. To address this question, we studied mice lacking RPE65, a protein essential for the regeneration of rod and cone pigments. Rpe65 ؊/؊ ipRGCs were Ϸ20-to 40-fold less photosensitive than normal at both single-cell and behavioral (PLR) levels but were rescued by exogenous 9-cis-retinal (an 11-cis-retinal analog), indicating the requirement of a vitamin A-based chromophore for ipRGC photosensitivity. In contrast, 9-cis-retinal was unable to restore intrinsic photosensitivity to melanopsin-ablated ipRGCs, arguing against melanopsin functioning merely in photopigment regeneration. Interestingly, exogenous all-trans-retinal was also able to rescue the low sensitivity of rpe65 ؊/؊ ipRGCs, suggesting that melanopsin could be a bistable pigment. Finally, we detected no melanopsin in the RPE and no changes in rod and cone sensitivities due to melanopsin ablation. Together, these results strongly suggest that melanopsin is the photopigment in the ipRGCs.RPE65 ͉ chromophore M elanopsin, an opsin-like protein, was first identified in dermal melanophores of Xenopus laevis (1) and subsequently was found in a small subset of retinal ganglion cells that is intrinsically photosensitive in mammals (2, 3). These intrinsically photosensitive retinal ganglion cells (ipRGCs) project predominantly to the suprachiasmatic nucleus (SCN), the intergeniculate leaflet, and the olivary pretectal nucleus (OPN) of the brain (3). These nuclei are important for circadian photoentrainment and the pupillary light reflex (PLR), accessory visual functions reporting ambient luminance rather than image formation on the retina. In melanopsin-knockout (opn4 Ϫ/Ϫ ) mice, the ipRGCs are present in normal numbers and project to the correct targets in the brain but are no longer intrinsically photosensitive (4). Thus, melanopsin is required for light detection by these cells. The PLR of opn4 Ϫ/Ϫ mice is also incomplete (4), and their circadian photoentrainment is attenuated (5, 6). In mice lacking both melanopsin and functional rods and cones, the PLR and circadian photoentrainment are abolished (7,8). Thus, the melanopsin-associated and rod-cone photoreceptive systems appear to account for all major non-image-forming visual functions.The action spectrum of the light response of ipRGCs can be fit by the absorption spectrum of a vitamin A-based photopigment with peak absorbance ( max ) at Ϸ484 nm (2). This action spectrum closel...

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Section: Discussionmentioning

confidence: 93%

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Zhong

Wang

et al. 2005

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

133

108

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“…There were no significant changes in sensitivity in the control eye. Pupillary reactions in the dark (21,22) also indicated increased light sensitivity in the study eyes of patients 2 and 3; this method showed no detectable change in sensitivity in the study eye of patient 1 or the control eyes of all three patients (Fig. S2).…”

Section: Human Gene Therapy Surmounts Biochemical Blockade In Rpe65-lcamentioning

confidence: 84%

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.

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606

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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“…All homozygous patients showed a complete loss of ERG responses and an abnormal pupillary reflex. However, a recordable reflex could be obtained in some of the homozygotes, suggesting that pupillometry may be one objective means of assessing and monitoring visual function in these patients as well as in patients who may benefit from future gene therapy [1]. In contrast, heterozygous patients showed normal visual function, ERG and pupillometry.…”

Section: Discussionmentioning

confidence: 99%

“…This protein is a retinol ester-binding protein that plays an important role in the vitamin A cycle, being necessary for the conversion to 11-cis retinal [7], the chromophore of the visual pigments. 1 Mice and dogs lacking RPE65 gene (knock-out model) have been developed and studied [22,28]. Histopathologic examinations of the diseased eyes from these animal models have revealed decreased accumulation of lipofuscin [11] and increased accumulation of retinyl esters in the RPE [16].…”

Section: Introductionmentioning

confidence: 99%

Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene

Matri¹,

Ambresin

Kawasaki

et al. 2006

Graefe's Arch Clin Exp Ophthalmo

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Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene Abstract Purpose: To identify the genetic defect and to phenotype three consanguineous Tunisian families presenting with early-onset retinal degeneration (EORD). Methods: All accessible family members were included. They underwent blood sampling and ophthalmological examination including, when possible, full-field ERG and pupillometry. A genomewide linkage analysis was initiated. Mutation analysis of the RPE65 gene within the linked interval was performed by bi-directional sequencing. Results: Eleven out of 53 examined members were clinically affected with an EORD. Linkage analysis revealed a maximal lod score of 4.02 (θ=0

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Impairment of the Transient Pupillary Light Reflex inRpe65^−/−Mice and Humans with Leber Congenital Amaurosis

Cited by 93 publications

References 59 publications

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

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

Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene

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Impairment of the Transient Pupillary Light Reflex inRpe65−/−Mice and Humans with Leber Congenital Amaurosis

Cited by 93 publications

References 59 publications

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

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

Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene

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Impairment of the Transient Pupillary Light Reflex inRpe65^−/−Mice and Humans with Leber Congenital Amaurosis