Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome

Krueger, Dilja D.; Bear, Mark F.

doi:10.1146/annurev-med-061109-134644

Cited by 241 publications

(198 citation statements)

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“…2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent negative modulator of mGluR5 [60], consistently rescues many FXSrelated deficits in KO mice [50,55,56,[61][62][63], fly [64][65][66] and zebrafish [67], implying the therapeutic potential of FXS using mGluR5 inhibitors. Indeed, multiple human clinical trials with chemicals targeting mGluR5, or mGluRs-related signaling pathways, or presynaptic release of glutamate, such as gamma-aminobutyric acid (GABA) B receptor agonists, are being conducted, and are showing promising, but as yet inconclusive, results with regard to treating FXS [68][69][70][71].…”

Section: Fragile X Mental Retardationmentioning

confidence: 99%

The complex genetics in autism spectrum disorders

Hua

Wei

Zhang

2015

Sci. China Life Sci.

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Autism spectrum disorders (ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants (CNVs), linkage regions, and microRNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.autism spectrum disorders, genetics, causative genes, copy number variants Citation:Hua R, Wei MP, Zhang C. The complex genetics in autism spectrum disorders. Sci China Life Sci, 2015, 58: 933 -945,

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Section: Fragile X Mental Retardationmentioning

confidence: 99%

The complex genetics in autism spectrum disorders

Hua

Wei

Zhang

2015

Sci. China Life Sci.

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“…"We might find a hundred things wrong with the brain function, but only one or two cause changes in behaviour, so we want to fix things and see what changes the behaviour, " says Powell. In work that has become a touchstone for the field, Mark Bear, a neuroscientist at the Massachusetts Institute of Technology (MIT) in Cambridge, and his colleagues showed that reducing expression of a particular receptor in mice ameliorated the effects of a mutation that causes fragile X syndrome 1 . Several physiological abnormalities were reversed, and engineered mice had fewer seizures and better memories.…”

Section: By M O N Ya B a K E Rmentioning

confidence: 99%

Inside the minds of mice and men

Baker

2011

Nature

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“…The animal data show that many aspects of FXS can be accounted for by altered Gp1 mGluR signaling at synapses. This insight is the basis for multiple clinical trials that are now underway in FXS (for extensive reviews see Bhakar et al [1] and Krueger and Bear [3]). …”

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confidence: 99%

“…One strategy for reducing mGluR activation is to suppress glutamate release at excitatory synapses, and this can be achieved by the activation of GABA B receptors. Early studies based on this idea showed that the GABA receptor agonist baclofen could drastically reduce the incidence of audiogenic seizures in Fmr1 -/y mice (reviewed in Krueger and Bear [3]). Schematic shows how mGluR signaling is targeted to treat FXS.…”

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confidence: 99%

“…The phospholipase C (PLC) and glycogen synthase kinase 3 (GSK3) signaling pathways are both stimulated by Gp1 mGluR activation, and the latter is hyperactive in theFmr1 -/y .Preclinical studies show that lithium ,a drug that inhibits PLC and GSK3, can correct multiple phenotypes in the Fmr1 -/y , and an open-label clinical trial showed behavioral improvements in FXS patients (for review, see Krueger and Bear [3]). Another important pathway activated by Gp1 mGluRs is the extracellular signalregulated kinase 1/2 (ERK1/2) signaling cascade, which is activated by the G-protein Ras, which leads to the sequential phosphorylation of Raf1 and MEK1/2.…”

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confidence: 99%

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Lifting the Mood on Treating Fragile X

Osterweil

Kind

Bear

2012

Biological Psychiatry

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Only a decade ago, it was believed that a genetic diagnosis of intellectual disability and autism offered little in the way of hope for a medical treatment to lessen the burden on the affected individuals and their families. However, recent research aimed at understanding the cellular and molecular mechanisms that underlie the pathogenesis of ASD has ushered in a new era of targeted treatment strategies. Studies in fragile X syndrome (FXS) have been at the forefront of this revolution, and they are forging a path that could define future approaches to the treatment of ASD.FXS is the leading identified genetic cause of autism. Because it is a defined genetic disorder that can be effectively modeled in animals, the study of FXS has great potential to yield information about the pathophysiology of ASD. FXS is caused by a silencing of the FMR1 gene and the loss of fragile X mental retardation protein (FMRP), a repressor of mRNA translation. Early studies suggested that synaptic protein synthesis is stimulated by activation of group 1 (Gp1) metabotropic glutamate receptors (comprising mGluR1 and mGluR5) and that one functional consequence of this protein synthesis is the longterm depression (LTD) of synaptic strength (reviewed in in Bhakar et al. [1]). The subsequent discovery that LTD is elevated in the mouse model of FXS (Fmr1 -/y ) led to the proposal that multiple symptoms of the disease might be accounted for by heightened responsiveness to Gp1 mGluR activation. This mGluR theory of fragile X predicted that the antagonism of Gp1 mGluRs should correct pathologic changes in FXS (2). In the decade that elapsed since it was first proposed, numerous studies in a range of animal models have validated this theory. The animal data show that many aspects of FXS can be accounted for by altered Gp1 mGluR signaling at synapses. This insight is the basis for multiple clinical trials that are now underway in FXS (for extensive reviews see Bhakar et al. [1] and Krueger and Bear [3]).The first clinical test of the mGluR theory was a small, open-label trial using fenobam, a Gp1 mGluR antagonist that is highly selective for mGluR5. The results of this small trial showed beneficial effects on a subset of the adult FXS patients tested; however, it is important to note that no placebo control group was included in this trial, nor was it performed in an experimenter blind fashion (4). Since this initial study, multiple largescale placebo-controlled trials have been initiated with selective mGluR5 negative allosteric modulators-namely, STX107 (Seaside Therapeutics, Cambridge, Massachusetts), RG7090 (Hoffman-LaRoche, Basel, Switzerland), and AFQ056 (Novartis, Basel, Switzerland). Although the results of most of these trials have yet to be revealed, in post hoc analysis of Phase II data AFQ056 was reported to show an improvement on multiple behavioral tests in adult patients with a fully methylated (silenced) FMR1 gene.In tandem with drugs that directly interfere with mGluR5, other drugs that may indirectly target Gp1 mGluR signaling a...

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Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome

Cited by 241 publications

References 98 publications

The complex genetics in autism spectrum disorders

The complex genetics in autism spectrum disorders

Inside the minds of mice and men

Lifting the Mood on Treating Fragile X

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