Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder.

Manuela Loi,Stefania Trazzi,Andrea Milelli,Giuseppe Galvani,Marianna Tassinari,Giorgio Medici,Laura Gennaccaro,Nicola Mottolese,Elisabetta Ciani,Claudia Fuchs,Roberto Rimondini Giorgini

doi:10.3390/ijms22115950

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.

Highlights

cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a complex and severe neurodevelopmental disorder caused by mutations of the CDKL5 gene [1], for which a cure is not available.Patients with CDKL5 deficiency disorder (CDD) are characterized by early-onset seizures and severe cognitive, motor, visual, and autonomic disturbances [1,2,3,4]
Our study provides novel evidence that, in in vitro experimental models of CDD, the GSK-3β/histone deacetylase 6 (HDAC6) dual inhibitor, Compound 11 (C11) [29], is more effective at recovering neuronal survival than treatment with a single inhibitor that is selective for GSK-3β
The deleterious effects caused by drug–drug interactions and toxicity of combination therapy have reinforced the emergence of novel strategies in drug discovery

Summary

Introduction

CDKL5 deficiency disorder (CDD) is a complex and severe neurodevelopmental disorder caused by mutations of the CDKL5 gene [1], for which a cure is not available.Patients with CDD are characterized by early-onset seizures and severe cognitive, motor, visual, and autonomic disturbances [1,2,3,4]. CDKL5 deficiency disorder (CDD) is a complex and severe neurodevelopmental disorder caused by mutations of the CDKL5 gene [1], for which a cure is not available. Genetic mutations of the CDKL5 gene cause absence of a functional CDKL5 protein, a serine/threonine kinase that is highly expressed in the brain and, in particular, in neurons [6,7]. CDKL5 has been found to regulate neuronal migration, axon outgrowth, dendritic morphogenesis, and synapse development in cultured rodent neurons as a model system [8,9,10,11,12]. Cdkl deficiency in mice impairs spine maturation and dendritic arborization of hippocampal and cortical neurons [13,14,15,16,17,18], indicating that CDKL5 plays a role in dendritic morphogenesis and synapse development. CDKL5 has been shown to regulate cell survival [19,20,21]

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