The Effect of Light Deprivation in Patients With Stargardt Disease

Teussink, Michel; Lee, Michele; Rjh, Smith; Huet, Ramon A. C. van; Klaver, Caroline C.W.; Klevering, B. Jeroen; Theelen, Thomas; Hoyng, Carel B.

doi:10.1016/j.ajo.2015.02.004

Cited by 33 publications

(29 citation statements)

References 36 publications

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“…Because the photodegradative processes examined here could over time be responsible for cumulative damage to retina and Bruch's membrane, the present findings have implications with respect to development of therapeutics that address bisretinoid lipofuscin deposition in recessive Stargardt disease and AMD (55)(56)(57)(58)(59)(60) and justify efforts to protect the retina of STGD1 patients by reducing light exposure through the use of a black contact lens (61). Quantitative Fundus Autofluorescence.…”

Section: Discussionmentioning

confidence: 85%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

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

111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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Section: Discussionmentioning

confidence: 85%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

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

111

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“…We only included patients with a reported disease onset <12 years of age [4, 5]. We excluded (1) patients with very early disease in which only thickening of the external limiting membrane was present, because this would preclude the OCT measurements, (2) patients with advanced disease characterized by RPE atrophy beyond the vascular arcades at first presentation, and (3) patients who participated in an interventional trial [40]. This study was approved by the local ethics committee on Research Involving Human Subjects of the Radboud university medical center “Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen” and the National Research Ethics Service (NRES) Committee London—Camden & Islington, and was performed in accordance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

Lambertus¹,

Bax²,

Fakin³

et al. 2017

PLoS ONE

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BackgroundEach inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration.Methods and findingsWe used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients.ConclusionsThese results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

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“…About half of the GPS+ patients carried a monoallelic ABCA4 variant, whereas only 10% of the GPS-patients carried these variant alleles 137 . Of note, light deprivation might contribute to reduced progression of decreased autofluorescence in STDG1 patients 191 .…”

Section: The Abca4 Gene and Clearance Of All-trans-retinalmentioning

confidence: 99%

Photo-damage, photo-protection and age-related macular degeneration

Marquioni-Ramella

Suburo

2015

Photochem Photobiol Sci

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Age-related macular degeneration (AMD) is a degenerative retinal disease that causes blindness in people 60-65 years and older, with the highest prevalence appearing in people 90 years-old or more. Epidemiological estimates indicate that the number of cases is increasing, and will almost double in the next 20 years. Preventive measures require precise etiological knowledge. This is quite difficult, since AMD is a multifactorial condition with intricate relationships between causes and risk factors. In this review, we describe the impact of light on the structure and physiology of the retina and the pigment epithelium, taking into account the continuous exposure to natural and artificial light sources along the life of an individual. A large body of experimental evidence demonstrates the toxic effects of some lighting conditions on the retina and the pigment epithelium, and consensus exists about the importance of photo-oxidation phenomena in the causality chain between light and retinal damage. Here, we analyzed the transmission of light to the retina, and compared the aging human macula in healthy and diseased retinas, as shown by histology and non-invasive imaging systems. Finally, we have compared the putative retinal photo-sensitive molecular structures that might be involved in the genesis of AMD. The relationship between these compounds and retinal damage supports the hypothesis of light as an important initiating cause of AMD.

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The Effect of Light Deprivation in Patients With Stargardt Disease

Cited by 33 publications

References 36 publications

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

Photo-damage, photo-protection and age-related macular degeneration

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