Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

doi:10.3389/fncel.2015.00055

Cited by 22 publications

(13 citation statements)

References 326 publications

(490 reference statements)

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“…2 Newer second-generation drugs acting at metabotropic glutamate and GABA B receptors rely on single molecular targets, and were expected to be more effective in alleviating selected symptoms. 1,3,4 However, to date, none of the small molecule drugs tested have shown convincing efficacy in Phase II clinical trials for FXS or autism. 5,6 Given that FMRP regulates the stability and translation of hundreds of mRNAs in the CNS, 7,8 these narrowly defined molecular treatment strategies have not addressed the core underlying issue: the absence or reduction of FMRP in the brain.…”

Section: Introductionmentioning

confidence: 99%

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector–based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels. The objective of this study was to investigate the consequences of expressing varying levels of FMRP selectively in neurons of Fmr1 knockout and wild-type (WT) mice. A wide range of neuronal FMRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP. In all treated knockout mice, prominent FMRP transgene expression was observed in forebrain structures, whereas lower levels were present in more caudal regions of the brain. Reduced levels of the synaptic protein PSD-95, elevated levels of the transcriptional modulator MeCP2, and abnormal motor activity, anxiety, and acoustic startle responses in Fmr1 knockout mice were fully or partially rescued after expression of FMRP at about 35–115% of WT expression, depending on the brain region examined. In the WT mouse, moderate FMRP over-expression of up to about twofold had little or no effect on PSD-95 and MeCP2 levels or on behavioral endophenotypes. In contrast, excessive over-expression in the Fmr1 knockout mouse forebrain (approximately 2.5–6-fold over WT) induced pathological motor hyperactivity and suppressed the startle response relative to WT mice. These results delineate a range of FMRP expression levels in the central nervous system that confer phenotypic improvement in fragile X mice. Collectively, these findings are pertinent to the development of long-term curative gene therapy strategies for treating Fragile X Syndrome and other neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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“…Although genetic treatment strategies have been successful in the laboratory setting, their clinical application is still hypothetical. Consequently, most of the emphasis on novel treatment development has focused on pharmacological approaches targeting processes downstream to the primary genetic abnormality [1,2]. Perhaps, the best-studied neurodevelopmental disorder from this targeted therapeutics perspective has been fragile X syndrome (FXS).…”

Section: Introductionmentioning

confidence: 99%

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Kaufmann

Stallworth

Everman

et al. 2016

Expert Opinion on Orphan Drugs

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Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.

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“…MMP9 or PAK), and (iv) the endocannabinoid system (1)(2)(3)(4). It is likely that additional therapeutic targets will be designed, if feasible, against Dgkκ (6).…”

Section: Significancementioning

confidence: 99%

“…FXS affects ∼1 in 2,500-5,000 men and 1 in 4,000-6,000 women and remains without effective pharmacological treatment (1)(2)(3)(4). Thus, the discovery of new targets and drugs that could normalize mental abilities is a great current challenge.…”

mentioning

confidence: 99%

“…Studies in animal models have revealed defects in multiple neurotransmitter systems and related signaling pathways (1)(2)(3)(4). These studies have led to the development of potential therapeutic agents that target (i) neurotransmitter/neuromodulator systems (such as metabotropic glutamate receptors, mGluRs, or GABAergic receptors), (ii) signaling pathways downstream of neurotransmitter receptors (such as MAPKs, PI3K, mTOR, and GSK3), (iii) proteins regulated by FMRP (such as…”

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confidence: 99%

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Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Mansilla

Chaves-Sanjuán

Campillo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The protein complex formed by the Ca 2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.fragile X syndrome | synapse regulation | NCS-1 | protein-protein interaction inhibitor | X-ray crystallography

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Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

Cited by 22 publications

References 326 publications

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

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