Vitamin A cycle byproducts impede dark adaptation

Zhang, Dan; Robinson, Kiera; Saad, Leonide; Washington, Ilyas

doi:10.1016/j.jbc.2021.101074

Cited by 4 publications

(6 citation statements)

References 53 publications

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“…1B), when measured 2 weeks after injection, indicating normal retinal homeostasis in regards to vitamin A. From about 2 weeks after injection onward, the ratio of A2E relative to vitamin A (the sum of retinol, retinaldehyde, retinyl esters) in the A2E-treated eyes was similar to that found in humans after the seventh decade of life (Zhang et al, 2021).…”

Section: Intravitreally Injected A2e Reaches the Rpe And The Neural Retinasupporting

confidence: 70%

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

2021

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In the most prevalent retinal diseases, including Stargardt disease and age-related macular degeneration (AMD), byproducts of vitamin A form in the retina abnormally during the vitamin A cycle. Despite evidence of their toxicity, whether these vitamin A cycle byproducts contribute to retinal disease, are symptoms, beneficial, or benign has been debated. We delivered a representative vitamin A byproduct, A2E, to the rat's retina and monitored electrophysiological, histological, proteomic, and transcriptomic changes. We show that the vitamin A cycle byproduct is sufficient alone to damage the RPE, photoreceptor inner and outer segments, and the outer plexiform layer, cause the formation of sub-retinal debris, alter transcription and protein synthesis, and diminish retinal function. The presented data are consistent with the theory that the formation of vitamin A byproducts during the vitamin A cycle is neither benign nor beneficial but may be sufficient alone to cause the most prevalent forms of retinal disease. Retarding the formation of vitamin A byproducts could potentially address the root cause of several retinal diseases to eliminate the threat of irreversible blindness for millions of people.

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Section: Intravitreally Injected A2e Reaches the Rpe And The Neural Retinasupporting

confidence: 70%

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

2021

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“…causing photoreceptor loss and functional deficits [23]. According to Zhang et al, vitamin A byproducts such as A2E may compete with vitamin A, even binding to RPE65 and retinoic acid receptor [69]. This could then inhibit opsins, interfering with the phototransduction cycle and leading to delayed dark adaptation [69].…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD

Akula,

McNamee,

Love

et al. 2024

Gene Ther

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Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4−/−) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.

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“…However, these animals have a fraction of VAB compared to humans. 33 The VAB presumably did not form in sufficient amounts to cause the advanced disease.…”

Section: Discussionmentioning

confidence: 99%

“…Fundus autofluorescence, quantification of qVAB, and electroretinography were performed. 31 , 33 , 40 , 41 …”

Section: Methodsmentioning

confidence: 99%

“…We have administered C20D 3 -vitamin A to swine, mice, rats, and mouse models of Stargardt disease, Abca4 − / − mice. 30 – 33 In Abca4 − / − mice, C20D 3 -vitamin A corrected the accelerated rate of vitamin A dimerization down to the rate observed in unaffected, wild-type mice. This rate correction correlated with a reduction in changes typically observed in the prodromal phase of human retinal degeneration, notably inflammation, the accumulation of lipofuscin in the RPE, complement activation, age-related declines in electroretinography (ERG) amplitudes, and delayed dark adaptation.…”

Section: Introductionmentioning

confidence: 97%

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C20D₃-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model

Zhang

Robinson

Washington

2021

Trans. Vis. Sci. Tech.

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Purpose This study aimed to evaluate the contribution of vitamin A dimerization to retinal pigment epithelium (RPE) atrophic changes. Leading causes of irreversible blindness, including Stargardt disease and age-related macular degeneration (AMD), occur as a result of atrophic changes in RPE. The cause of the RPE atrophic changes is not apparent. During the vitamin A cycle, vitamin A dimerizes, leading to vitamin A cycle byproducts, such as vitamin A dimers, in the RPE. Methods To study the consequence of vitamin A dimerization to RPE atrophic changes, we used a rodent model with accelerated vitamin A dimerization, Abca4 −/− /Rdh8 −/− mice, and the vitamin A analog C20D 3 -vitamin A to selectively ameliorate the accelerated rate of vitamin A dimerization. Results We show that ameliorating the rate of vitamin A dimerization with C20D 3 -vitamin A mitigates pathological changes observed in the prodromal phase of the most prevalent retinal degenerative diseases, including fundus autofluorescence changes, dark adaptation delays, and signature RPE atrophic changes. Conclusions Data demonstrate that the dimerization of vitamin A during the vitamin A cycle is sufficient alone to cause the prerequisite RPE atrophic changes thought to be responsible for the leading causes of irreversible blindness and that correcting the dimerization rate with C20D 3 -vitamin A may be sufficient to prevent the RPE atrophic changes. Translational Relevance Preventing the dimerization of vitamin A with the vitamin A analog C20D 3 -vitamin A may be sufficient to alter the clinical course of the most prevalent forms of blindness, including Stargardt disease and age-related macular degeneration (AMD).

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Vitamin A cycle byproducts impede dark adaptation

Cited by 4 publications

References 53 publications

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD

C20D₃-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model

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Vitamin A cycle byproducts impede dark adaptation

Cited by 4 publications

References 53 publications

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD

C20D3-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model

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C20D₃-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model