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

Autor: Dorot O; Blavatnik Center for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel., Roux LN; INSERM U976, Hôpital St-Louis, Paris, France; Université de Paris, France., Zennaro L; Université de Paris, France; INSERM UMRS 1138, Team 17, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France., Oved K; Blavatnik Center for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel., Bremond-Gignac D; INSERM UMRS 1138, Team 17, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France; Ophthalmology Department, University Hospital Necker-Enfants malades, AP-HP, Paris, France., Pichinuk E; Blavatnik Center for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel. Electronic address: pichinuk@tauex.tau.ac.il., Aberdam D; INSERM U976, Hôpital St-Louis, Paris, France; INSERM UMRS 1138, Team 17, From physiopathology of ocular diseases to clinical development, Centre de Recherche des Cordeliers, Paris, France. Electronic address: daniel.aberdam@inserm.fr.
Jazyk: angličtina
Zdroj: The ocular surface [Ocul Surf] 2022 Jan; Vol. 23, pp. 140-142. Date of Electronic Publication: 2021 Dec 08.
DOI: 10.1016/j.jtos.2021.12.003
Abstrakt: Aniridia is a panocular disease causing progressive severe visual impairment and blindness due to PAX-6 haploinsufficiency. One of the most disabling ocular symptoms is aniridia-related keratopathy (ARK), a progressive corneal opacification due to epithelial impairment, vascular and conjunctival pathologies. There is currently no available treatment to prevent progressive visual loss. For this aim, we have used mutant limbal cells for phenotypic screening using FDA-approved and bio-actives drug library and found Duloxetine, a serotonin and norepinephrine reuptake inhibitor used against severe depression as able to enhance endogenous PAX6 expression and target genes, which returned fairly to amounts found in normal limbal cells. In addition, Duloxetine could restore cell migration of the mutant cells. Furthermore, we show that Duloxetine activates PAX6 through inhibition of the ERK pathway on limbal mutant cells. This observation fits the recent report that MEK inhibitors enhance PAX6 in vivo, partially rescuing aniridia developmental phenotype of Pax6 +/- mice. The discovery of an unique compound able to enhance PAX6 activity and that could be locally administered using eye drops associated with drug repurposing is expected to lead to rapid development of applicable drugs for the topical (eye drops) treatment of aniridia.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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