Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet’s signaling cascades as new outcome measures in clinical trials

Pellerin, David; Çaku, Artuela; Fradet, Mathieu; P, Bouvier; Dubé, Jean; Corbin, François

doi:10.3109/1354750x.2016.1160289

Cited by 44 publications

(41 citation statements)

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“…FMRP binds and acts as a repressor of translation of a number of mRNAs including those involved in the ERK cascade signaling pathway [74]; thus, the lack of this negative translational control is believed to lead to upregulation of these pathways and consequently to the altered synaptogenesis observed in FXS. Several studies have shown upregulation of ERK in both mouse and human (reviewed in [75]), who, contrary to our observations, recently reported a reduction of the ERK pathway signaling following a lovastatin treatment. Specifically, they reported 1.6-fold increase in basal ERK phosphorylation levels in blood platelets derived from subjects with FXS, which was rescued by lovastatin treatment and correlated with clinical response.…”

Section: Biomarkers Of Lovastatin-induced Changecontrasting

confidence: 99%

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome

Thurman

Potter

Kim

et al. 2020

J Neurodevelop Disord

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Background: The purpose of this study was to conduct a 20-week controlled trial of lovastatin (10 to 40 mg/day) in youth with fragile X syndrome (FXS) ages 10 to 17 years, combined with an open-label treatment of a parentimplemented language intervention (PILI), delivered via distance video teleconferencing to both treatment groups, lovastatin and placebo. Method: A randomized, double-blind trial was conducted at one site in the Sacramento, California, metropolitan area. Fourteen participants were assigned to the lovastatin group; two participants terminated early from the study. Sixteen participants were assigned to the placebo group. Lovastatin or placebo was administered orally in a capsule form, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. A PILI was delivered to both groups for 12 weeks, with 4 activities per week, through video teleconferencing by an American Speech-Language Association-certified Speech-Language Pathologist, in collaboration with a Board-Certified Behavior Analyst. Parents were taught to use a set of language facilitation strategies while interacting with their children during a shared storytelling activity. The main outcome measures included absolute change from baseline to final visit in the means for youth total number of story-related utterances, youth number of different word roots, and parent total number of story-related utterances.

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Section: Biomarkers Of Lovastatin-induced Changecontrasting

confidence: 99%

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome

Thurman

Potter

Kim

et al. 2020

J Neurodevelop Disord

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“…Remarkably, several targets of FMRP belong to the two major mGluR-signaling cascades controlling the expression of related proteins, the ERK 11 - and the mTOR 12 - pathway: ERK, PI3K 13 , PIKE 14 , GSK3 15 and mTOR are target mRNAs of FMRP (Darnell et al, 2011 ; Ascano et al, 2012 ). Both signaling pathways turned out to be exaggerated not only in the hippocampus of Fmr1 −/y mice (ERK pathway: Hou et al, 2006 ; Michalon et al, 2012 ; mTOR pathway: Sharma et al, 2010 ; Liu Z. H. et al, 2012 ; Bhattacharya et al, 2016 ; Choi et al, 2016 ), but also in humans (Weng et al, 2008 ; Hoeffer et al, 2012 ; Wang X. et al, 2012 ; Kumari et al, 2014 ; Pellerin et al, 2016 ).…”

Section: The Fragile X Syndrome — Of Micementioning

confidence: 99%

“…In fact, some data even suggest that mTOR inhibition with Rapamycin might cause neurodegeneration (Lin et al, 2013 ). The hopes are therefore now on clinical trials with Lovastatin (Caku et al, 2014 ; Pellerin et al, 2016 ) and Metformin (Dy et al, 2018 ).…”

Section: The Fragile X Syndrome — Of Micementioning

confidence: 99%

Of Men and Mice: Modeling the Fragile X Syndrome

Dahlhaus

2018

Front. Mol. Neurosci.

109

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The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research.

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“…Additionally, studies using the Fmr1 -/y rat model show that lovastatin treatment at a juvenile age can prevent the emergence of complex cognitive phenotypes [21]. Based on the positive outcome with lovastatin in Fmr1 -/y animal models, two open-label clinical trials tested the viability of lovastatin for the treatment of FX [22,23]. Both studies revealed a significant improvement with lovastatin treatment, and a double-blind placebocontrolled trial is ongoing [6].Interestingly, the availability of lovastatin is not widespread in Europe and is not licensed for use in the UK.…”

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confidence: 99%

Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model

Muscas

Louros

Osterweil

2018

Preprint

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The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1 -/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1 -/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX. Introduction:Fragile X syndrome (FX) is a monogenic neurodevelopmental disorder characterized by severe intellectual disability (ID), autism, hypersensitivity to sensory stimulation and epilepsy [1]. FX occurs in 1:4000 males and 1:8000 females, making it one of the most commonly identified genetic causes of autism and ID [1,2]. The FMR1 gene mutated in FX encodes Fragile X Mental Retardation Protein (FMRP), which represses mRNA translation in neurons [3,4]. Studies of the Fmr1 -/y mouse model of FX reveal that excessive cerebral protein synthesis is a major consequence of Fmr1 deletion [5-9], which can be normalized through antagonism of metabotropic glutamate receptor 5 (mGlu 5 ) or the downstream extracellular regulated kinase 1/2 (ERK1/2) MAP kinase signalling pathway [7,[10][11][12][13]. These strategies correct multiple neurological phenotypes in the Fmr1 -/y mouse, including an enhanced susceptibility to audiogenic seizures (AGS) [7,10,11,14]. The current challenge is to successfully transition these therapeutic approaches to the clinic.In previous work we showed that the statin drug lovastatin, currently used for the treatment of high cholesterol in adults and children, reduces ERK1/2 activation and resolves neuropathology in the Fmr1 -/y mouse model [15]. Lovastatin was the first statin drug developed and has been shown to be remarkably effective in lowering cholesterol with minimal side effects [16]. In FX, the therapeutic relevance of lovastatin is in the dampening of ERK1/2 signalling that occurs by reducing the activation of the upstream GTPase Ras [17,18]. By targeting the same mevalonate pathway that produces cholesterol, lovastatin limits the availability of farnesyl pyrophosphate precursor that is required for the membrane association and activation of Ras [17][18][19]. By this mechanism, lovastatin has been shown to successfully correct electrophysiological and behavioural phenotypes in the mouse model of Neurofibromatosis Type 1 (NF1), a neurodevelopmental disorder of excess Ras [20].In the Fmr1 -/y mouse, the reduction of Ras-ERK1/2 by lovastatin ameliorates hippocampal epileptogenesis and neocortical hyperexcitability and significantl...

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Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet’s signaling cascades as new outcome measures in clinical trials

Abstract: Platelets' signaling pathways provide biomarkers that can be used as treatment outcome measures in FXS clinical trials.

Cited by 44 publications

References 102 publications

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome

Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome

Of Men and Mice: Modeling the Fragile X Syndrome

Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model

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