The antipsychotropic drug Duloxetine rescues PAX6 haploinsufficiency of mutant limbal stem cells through inhibition of the MEK/ERK signaling pathway

Dorot, Orly; Roux, L.; Zennaro, Léa; Oved, Keren; Bremond-Gignac, Dominique; Pichinuk, Edward; Aberdam, Daniel

doi:10.1016/j.jtos.2021.12.003

Cited by 8 publications

(8 citation statements)

References 9 publications

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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%

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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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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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“…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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“…Employing an alternative strategy, it was recently shown that the antidepressant duloxetine enhances the expression of the PAX6 protein in human limbal stem cells (LSCs) 93 via the ERK/MEK pathway. The authors tested the effects of the repurposed drug in vitro in PAX6 gene-edited LSCs, with duloxetine enhancing PAX6 expression and normalizing the expression of the target genes normally repressed by PAX6 in mutant cells.…”

Section: Pax6/aniridiamentioning

confidence: 99%

Emerging Gene Manipulation Strategies for the Treatment of Monogenic Eye Disease

Burgess

Hall

Megaw

2022

Asia-Pacific Journal of Ophthalmology

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Genetic eye diseases, representing a wide spectrum of simple and complex conditions, are one of the leading causes of visual loss in children and working adults, and progress in the field has led to changes in disease investigation, diagnosis, and management. The past 15 years have seen the emergence of novel therapies for these previously untreatable conditions to the extent that we now have a licensed therapy for one form of genetic eye disease and many more in clinical trial. This is a systematic review of published and ongoing clinical trials of gene therapies for monogenic eye diseases. Databases of clinical trials and the published literature were searched for interventional studies of gene therapies for eye diseases. Standard methodological procedures were used to assess the relevance of search results. A total of 59 registered clinical trials are referenced, showing the significant level of interest in the potential for translation of these therapies from bench to bedside. The breadth of therapy design is encouraging, providing multiple possible therapeutic mechanisms. Some fundamental questions regarding gene therapy for genetic eye diseases remain, such as optimal dosing, the relative benefits of adeno-associated virus (AAV)–packaging and the potential for a significant inflammatory response to the therapy itself. As a result, despite the promise of the eye as a target, it has proven difficult to deliver clinically effective gene therapies to the eye. Despite setbacks, the licensing of Luxturna (voretigene neparvovec, Novartis) for the treatment of RPE65-mediated Leber congenital amaurosis (LCA) is a major advance in efforts to treat these rare, but devastating, causes of visual loss.

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The antipsychotropic drug Duloxetine rescues PAX6 haploinsufficiency of mutant limbal stem cells through inhibition of the MEK/ERK signaling pathway

Cited by 8 publications

References 9 publications

PAX6 disease models for aniridia

PAX6 disease models for aniridia

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Emerging Gene Manipulation Strategies for the Treatment of Monogenic Eye Disease

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