AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome

Levenga, Josien; Hayashi, Shigemi; Vrij, Femke M.S. de; Koekkoek, S.K.E.; Linde, Herma C. van der; Nieuwenhuizen, Ingeborg M.; Song, Cheng; Buijsen, Ronald A.M.; Pop, Andreea; Gomez‐Mancilla, Baltazar; Nelson, David L.; Willemsen, Rob; Gasparini, F.; Oostra, Ben A.

doi:10.1016/j.nbd.2011.01.022

Cited by 112 publications

(58 citation statements)

References 34 publications

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“…They also provide a cogent example of how context can dramatically impact the penetrance of otherwise devastating genetic changes. Consistent with the ability of a partial loss of mGluR5 to reverse cognitive deficits of Fmr1-deficient mice, the mGluR1/5 antagonist MPEP reverses multiple behavioral abnormalities in Fmr1-null mice (de Vrij et al, 2008;Levenga et al, 2011;Yan et al, 2005). Remarkably, Su et al (2011) recently reported that early, continuous, treatment with MPEP can even reverse dendritic spine abnormalities in Fmr1-KO mice.…”

Section: Path From Rare Genetic Syndromes To New Treatments In Asd Mtmentioning

confidence: 60%

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Veenstra‐VanderWeele

Blakely

2011

Neuropsychopharmacol

111

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Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor-and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.

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Section: Path From Rare Genetic Syndromes To New Treatments In Asd Mtmentioning

confidence: 60%

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Veenstra‐VanderWeele

Blakely

2011

Neuropsychopharmacol

111

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“…• 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%

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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“…Another indication of mavoglurant is the treatment of fragile X syndrome, which is caused by expansion of a CGG trinucleotide repeat in the 59 untranslated region of the fragile X mental retardation 1 (FMR1) gene. The fragile X syndrome is associated with intellectual disability and behavioral problems in children as well as adults (Levenga et al, 2011). In a recent study, it was shown that therapeutic blockage of mGLuR5 by mavoglurant can improve the behavioral symptoms in male adults with fragile X and that this improvement is predicted by full methylation at the fragile X mental retardation 1 promoter (Jacquemont et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Disposition of the Metabotropic Glutamate Receptor 5 Antagonist (mGluR5) Mavoglurant (AFQ056) in Healthy Subjects

et al. 2013

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The disposition and biotransformation of 14 C-radiolabeled mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine, and feces collected over 7 days were analyzed for total radioactivity, mavoglurant was quantified in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wetchemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ‡50% of dose reaching mean plasma C max values of 140 ng/ml (mavoglurant) and 855 ng-eq/ml (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of mavoglurant occurred predominantly by oxidative metabolism involving primarily 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven main metabolites, which combined accounted for 60% of 14 C-AUC 0-72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces.

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AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome

Cited by 112 publications

References 34 publications

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

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

Metabolism and Disposition of the Metabotropic Glutamate Receptor 5 Antagonist (mGluR5) Mavoglurant (AFQ056) in Healthy Subjects

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