Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice

Gantois, Ilse; Pop, Andreea; Esch, Celine de; Buijsen, Ronald A.M.; Pooters, Tine; Gomez‐Mancilla, Baltazar; Gasparini, F.; Oostra, Ben A.; D’Hooge, Rudi; Willemsen, Rob

doi:10.1016/j.bbr.2012.10.059

Cited by 88 publications

(66 citation statements)

References 55 publications

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“…For a more extensive review of Fmr1 knockout mice behavioral phenotypes see [180]. Behavior: social dominance [119]; sociability [132] Cognition: object recognition (chronic, not acute) [121]; fear conditioning [120]; associative motor learning (acute) [133]; inhibitory avoidance (chronic and acute) [129,133]; extinction memory (chronic) [129] LTP deficits in the amygdala and hippocampus (bath application) [128,134]; LTD (bath application) [135] startle response, † rotarod performance [131]; object recognition (acute) [121,134]; coordinate and categorical tasks (acute) [134]; analgesic response [121] mGlu5 NAMs used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

Section: Macro-orchidismmentioning

confidence: 99%

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Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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Section: Macro-orchidismmentioning

confidence: 99%

Section: Macro-orchidismmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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“…Specifically, the FXS mouse model (the FMR1 knockout) has shown that FXS can be "cured" (reversal of the excess protein synthesis) of the core phenotype after using agonists of GABA-B receptors [50] or mGluR5 antagonists [48]. To date, a total of 20 double-blind, randomized, placebo-controlled clinical trials in FXS have tested 13 compounds primarily targeting excitatory/inhibitory imbalance theory of FXS and ASD.…”

Section: Discussionmentioning

confidence: 99%

“…The effort has focused on identifying agents that restore the aforementioned excitatory/inhibitory balance in the FXS brain based on the 'mGluR5 theory,' in which disruptions in mGluR5 signaling are thought to underlie a dendritic pathology [44] and clinical presentations of FXS [14]. Namely, the 'gold-standard' rescue of the dendritic pathology in FXS has been demonstrated in the Fmr1-knockout mouse that largely centered on the use of mGluR5 antagonists [48,49] and GABA-B agonists [50]. These studies of mGluR5 antagonists further support the mGluR5 theory [44].…”

Section: Neurobiological Features and Targeted Treatments In Fragile mentioning

confidence: 99%

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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“…It is now widely accepted that the loss of FMRP allows for excessive mGluR5 signaling, which in turn results in excessive protein translation and synthesis. Continuous treatment of FMRP mutant mice with mGluR5 inhibitors commencing early in life eliminate seizure and other phenotype abnormalities (19,20). These findings have provided a foundation and led to development of potent and selective mGluR5 inhibitors, including AFQ056, RG7090 and STX209, which have advanced into human clinical studies (21)(22)(23).…”

Section: Scientific Rationale For Development Of Personalized Pharmacmentioning

confidence: 99%

Fragile X syndrome as a rare disease in China – Therapeutic challenges and opportunities

Jin

Chen

2015

IRDR

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Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice

Cited by 88 publications

References 55 publications

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Fragile X syndrome as a rare disease in China – Therapeutic challenges and opportunities

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