Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65

Lorenz, Birgit; Wabbels, Bettina; Wegscheider, E.; Hamel, Christian; Drexler, Wolfgang; Preising, Markus N.

doi:10.1016/j.ophtha.2004.01.033

Cited by 150 publications

(119 citation statements)

References 31 publications

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“…32 In various degenerative retinal disorders, increased FAF correlated with lipofuscin accumulation, whereas reduced or absent FAF indicated blockage (eg, retinal vessels), loss of RPE cells, or absence of RPE phagocytosis. 26,27,[33][34][35][36][37][38][39][40] The patterns of FAF distribution in RP patients observed in this study are similar to those reported previously. Ophthalmoscopically preserved areas of RPE at the posterior pole correspond to detectable FAF.…”

Section: Discussionsupporting

confidence: 86%

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa

Kellner

Weber

et al. 2008

Eye

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Aims To compare melanin-related nearinfrared fundus autofluorescence (FAF; NIA, excitation 787 nm, emission 4800 nm) with lipofuscin-related FAF (excitation 488 nm, emission 4500 nm) in retinitis pigmentosa (RP). Methods Thirty-three consecutive RP patients with different modes of inheritance were diagnosed clinically, with full-field ERG, and if possible with molecular genetic methods. FAF and NIA imaging were performed with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2). Results Rings of increased FAF were present within an area of preserved retinal pigment epithelium (RPE) at the posterior pole (31/33). Rings of increased NIA were located in the same region as rings of increased FAF. In contrast to FAF, NIA showed a precipitous decline of NIA peripheral to the ring. In larger areas of preserved NIA (11/31), pericentral and foveal NIA were of similar intensity with an area of lower NIA in between. In smaller areas of preserved NIA (20/31), NIA was homogeneous from the perifovea to the fovea. In one patient without a ring of increased FAF, NIA distribution was normal. In the remaining patient with severely advanced RP, no residual RPE as well as no FAF and NIA were detectable. Conclusion Characteristic features for FAF and NIA alterations in a heterogeneous group of RP patients indicate a common pathway of RPE degeneration. Patterns of NIA and FAF indicate different pathophysiologic processes involving melanin and lipofuscin. Combined NIA and FAF imaging will provide further insight into the pathogenesis of RP and noninvasive monitoring of future therapeutic interventions.

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Section: Discussionsupporting

confidence: 86%

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa

Kellner

Weber

et al. 2008

Eye

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“…The progression rate in RPE65-mutant dogs averaged −0.33 log 10 /y, corresponding to −0.05 log 10 /human y. Thus, both murine and canine models show an extended period (up to 25% of their lifespan) with a retinawide dysfunction-only phase that does not seem to have an equivalent in human RPE65-LCA at any age observed to date (6,(19)(20)(21)(22)(23)(24)(43)(44)(45). Human RPE65-LCA is best modeled in older animals clearly displaying the dysfunction as well as degeneration phases of RPE65 disease.…”

Section: Discussionmentioning

confidence: 93%

“…Rpe65 −/− mice show an onset of degeneration near 3-4 mo (4, 42) and a degeneration rate averaging −0.22 log 10 /y (21). Assuming an allometric relationship between rates of neurodegeneration and maximum lifespan (33), the Rpe65 −/− mouse disease is much slower than human disease (6,(19)(20)(21)(22)(23)(24)(43)(44)(45), with an onset that is equivalent to 9-12 human y and a rate that corresponds to −0.006 log 10 /human y. RPE65-mutant dogs were also known to have slow photoreceptor degeneration (5,29,30,32), but the details of spatiotemporal progression were unknown. Our results showed that the onset of degeneration ranges from 5 to 8 y depending on retinal location.…”

Section: Discussionmentioning

confidence: 99%

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

Cideciyan

Jacobson

Beltran

et al. 2013

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

394

384

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Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.neurodegeneration | outer nuclear layer | retinal structure

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“…Humans with RPE65 deficiency have been suspicious for having complexity of disease mechanism: there is extremely reduced photoreceptor function and visual loss from early life, but there can be hallmarks of pigmentary degeneration and atrophy of the retina (2,3,(33)(34)(35)(36)(37)(38)(39)(40). The reduced vision is consistent with two possible disease mechanisms or a combination thereof: (i) an interrupted retinoid cycle that is potentially treatable by RPE65 gene replacement, RPE cell replacement, supplemental cis-retinoids, or any means to reestablish the biochemical pathway (1), and (ii) loss of photoreceptors, which would be more appropriate for therapeutic strategies such as visual prosthetics (41).…”

Section: Discussionmentioning

confidence: 99%

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success

Jacobson

Alemán

Cideciyan

et al. 2005

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

249

279

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Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65 ؊/؊ mice at advanceddisease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.visual cycle ͉ Leber congenital amaurosis ͉ rod ͉ cone ͉ retinal imaging

show abstract

Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65

Cited by 150 publications

References 31 publications

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success

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