Ritanserin, a potent serotonin 2A receptor antagonist, represses MEK/ERK signalling pathway to restore PAX6 production and function in aniridia-like cellular model

Oved, Keren; Zennaro, Léa; Dorot, Orly; Zerbib, Johanna; Frank, Elie; Roux, L.; Brémond‐Gignac, Dominique; Pichinuk, Edward; Aberdam, Daniel

doi:10.1016/j.bbrc.2021.10.036

Cited by 8 publications

(7 citation statements)

References 15 publications

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“…In a case report from Japan, a one-month-old infant with WAGR had microcornea with a pronounced corneal cyst in one eye, and Grade 3 AAK in the other ( Kawase et al, 2001 ). This population could therefore be considered as a preferred target group for the first new AAK therapies aiming to compensate for PAX6 haploinsufficiency by overexpression of the non-mutant allele ( Dorot et al, 2022 ; Oved et al, 2021 ; Rabiee et al, 2020 ). The rationale is that in the non-WAGR population, AAK takes decades to progress, making timing and duration of therapy and follow-up difficult for initial clinical trials designed to demonstrate efficacy in slowing down the progression or reversing the AAK phenotype.…”

Section: Genetics Of Aniridia and Aniridia-like Disordersmentioning

confidence: 99%

Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

Daruich

Duncan

Robert³

et al. 2023

Progress in Retinal and Eye Research

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Section: Genetics Of Aniridia and Aniridia-like Disordersmentioning

confidence: 99%

Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

Daruich

Duncan

Robert³

et al. 2023

Progress in Retinal and Eye Research

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“…[ 73 74 75 76 ] MEK/extracellular signal-regulated kinases (ERK) signaling pathway repressor drugs, duloxetine and ritanserin, have been recently tested on mutant LESCs and have shown to rescue PAX6 haploinsufficiency and restore PAX6 production. [ 77 78 ]…”

Section: Human Cellular Modelsmentioning

confidence: 99%

“…The advantage of these drugs would be their availability and not being selective on the type of mutation. [ 58 77 78 ] From a practical clinical perspective, family planning and preimplantation genetic diagnosis should be discussed with prospective parents.…”

Section: Management Of Aniridia and Potential Clinical Prospectsmentioning

confidence: 99%

PAX6 disease models for aniridia

Abdolkarimi

Cunha²,

Lahne

et al. 2022

Indian Journal of Ophthalmology

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Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.

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“…This cellular model was, therefore, subsequently used to screen for drugs able to rescue Pax6 by increasing its endogenous production in cells. Among the selected hits, Duloxetine and Ritanserin, two anti-psychotropic small compounds, were identified in the in vitro AAK cellular model as being able to restore PAX6 gene expression and limbal cell functional properties [175,176]. Of interest, both drugs re-activated PAX6 gene expression through specific MEK and ERK inhibition, respectively [175,176].…”

Section: Mapk In the Corneamentioning

confidence: 99%

“…Among the selected hits, Duloxetine and Ritanserin, two anti-psychotropic small compounds, were identified in the in vitro AAK cellular model as being able to restore PAX6 gene expression and limbal cell functional properties [175,176]. Of interest, both drugs re-activated PAX6 gene expression through specific MEK and ERK inhibition, respectively [175,176]. This was supported by the finding that PAX6 gene expression is down-regulated by EGF to allow for proper corneal epithelial proliferation, while the overexpression of PAX6 in these cells attenuated EGF-induced proliferation [177].…”

Section: Mapk In the Corneamentioning

confidence: 99%

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Moustardas

Aberdam

Lagali

2023

Cells

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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additionally, we discuss challenges in overcoming the reported eye toxicity of some MAPK inhibitors.

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Ritanserin, a potent serotonin 2A receptor antagonist, represses MEK/ERK signalling pathway to restore PAX6 production and function in aniridia-like cellular model

Cited by 8 publications

References 15 publications

Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

PAX6 disease models for aniridia

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

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