Penetration, distribution, and elimination of remofuscin/soraprazan in Stargardt mouse eyes following a single intravitreal injection using pharmacokinetics and transmission electron microscopic autoradiography: Implication for the local treatment of Stargardt’s disease and dry age‐related macular degeneration

Julien-Schraermeyer, Sylvie; Illing, Barbara; Tschulakow, Alexander; Taubitz, Tatjana; Guezguez, Jamil; Burnet, Michael; Schraermeyer, Ulrich

doi:10.1002/prp2.683

Cited by 22 publications

(15 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the proton pump which is inhibited by remofuscin is not present in the RPE in the eyes of human, proton pump inhibitors are known to increase the lysosomal pH, thereby activating transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, and inducing lysosomal exocytosis and autophagy 37 . Remofuscin binds to lipofuscin 38 and is a superoxide generator when illuminated with light 39 . Superoxide might help to degrade the polymeric lipofuscin into smaller units which then are transported out of the lysosomes by exocytosis.…”

Section: Discussionmentioning

confidence: 99%

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Yeom

Schraermeyer

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly (p < 0.05) extended the lifespan of C. elegans (N2) compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms. The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans. In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.

show abstract

Section: Discussionmentioning

confidence: 99%

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Yeom

Schraermeyer

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…To prepare for embedding, the eyecups were cut vertically into two halves through the optic disc after removing the cornea and lens. The eyes are embedded in Epon resin and later sectioned according to standard procedures[1, 20]. Reagents were purchased from AppliChem (Darmstadt, Germany), Serva (Heidelberg, Germany) and Merck (Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Lyu¹,

Tschulakow²,

Schraermeyer³

2022

Preprint

Self Cite

View full text Add to dashboard Cite

The accumulation of the age pigment lipofuscin within the retinal pigment epithelium (RPE) is one the most remarkable changes observed in association with age-related macular degeneration (AMD) and Stargardt disease. Both aging and pathological processes lead to the accumulation of melanolipofuscin (MLF) granules, which have been reported to reflect the onset of AMD more accurately than lipofuscin. The underlying mechanism by which MLF forms is still not understood. We investigate the potential role that melanin plays in the degradation of lipofuscin and MLF in pigmented Abca4-/- mice following treatment with several NO generating drugs. Abca4-/- mice are generally used as models for lipofuscin-related eye diseases. We also induced melanogenesis in albino Abca4-/- mice via the over-expression of tyrosinase, the key enzyme involved in melanogenesis. We compared the ultrastructure of lipofuscinogensis in the RPE of pigmented and albino Abca4-/- mice. Fluorescence microscopy was employed for the quantification of lipofuscin. We found high amounts of unique thin (3-4 nm) lamellar membranes (TLMs) that were left over from the degradation of photoreceptor disc membranes by high-resolution electron microscopy. Accumulated TLMs were significantly more frequent in the RPE cells of the albinos than the pigmented mice, indicating that melanin plays a role in removing TLMs. The intravitreal injection of several NO generating drugs was found to reduce the amount of autofluorescent lipofuscin in the cytoplasm of RPE cells, particularly the MLF granules of pigmented Abca4-/- mice. No effect was observed in terms of lipofuscin removal in NO-exposed albino Abca4-/- mice. However, transfection with tyrosinase led to a reduction in the lipofuscin levels of artificially pigmented RPE cells in albino Abca4-/- mice following the formation of melanin. The results show for the first time that melanin plays an important, if not a key, role in the degradation of lipofuscin in RPE cells.

show abstract

“…It is a small molecule that can remove lipofuscin from RPE cells. It has been tested in an animal model of lipofuscinogenis [ 535 ] and a multi-national, multi-center, double-masked, placebo-controlled, proof-of-concept trial is evaluating the safety and efficacy of oral soraprazam in Stargardt disease (EudraCT 2018-001496-20).…”

Section: Therapeutic Strategies To Reduce Oxidative Stress and Inflam...mentioning

confidence: 99%

Inherited Retinal Dystrophies: Role of Oxidative Stress and Inflammation in Their Physiopathology and Therapeutic Implications

et al. 2022

View full text Add to dashboard Cite

Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species’ accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation.

show abstract

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 22 publications

References 39 publications

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Inherited Retinal Dystrophies: Role of Oxidative Stress and Inflammation in Their Physiopathology and Therapeutic Implications

Contact Info

Product

Resources

About