Fragile X targeted pharmacotherapy: Lessons learned and future directions

Journal of Neurodevelopmental Disorders

Volumn 9, Issue 1, 2017, Pages

  Erickson, Craig A ^a,b   Davenport, Matthew H ^a,c   Schaefer, Tori L ^a   Wink, Logan K ^a,b   Pedapati, Ernest V ^a,b   Sweeney, John A ^b   Fitzpatrick, Sarah E ^a   Brown, W Ted ^j   Budimirovic, Dejan ^k   Hagerman, Randi J ^d,e   Hessl, David ^d,f   Kaufmann, Walter E ^g,h   Berry Kravis, Elizabeth ⁱ  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^b UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

^c University of Cincinnati   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f UNIVERSITY OF CALIFORNIA   (United States)

^g GREENWOOD GENETIC CENTER   (United States)

^h BOSTON CHILDREN S HOSPITAL   (United States)

ⁱ RUSH UNIVERSITY MEDICAL CENTER   (United States)

^j NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

^k DEPARTMENT OF PATHOLOGY   (United States)

more..

Author keywords

Drug development; Fragile X syndrome; Genetic disorder; Targeted treatments; Translational treatment

Indexed keywords

4 AMINOBUTYRIC ACID; GLUTAMIC ACID; LITHIUM; METADOXINE; MEVINOLIN; MINOCYCLINE;

CLINICAL TRIAL (TOPIC); DRUG DEVELOPMENT; DRUG TARGETING; FRAGILE X SYNDROME; HUMAN; NEUROMODULATION; NEUROPHARMACOLOGY; NEUROTRANSMISSION; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW;

EID: 85020725021     PISSN: 18661947     EISSN: 18661955     Source Type: Journal    
DOI: 10.1186/s11689-017-9186-9     Document Type: Review

References (143)

1. Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet. 1996;64(1):196-7.
2. Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess. 2003;7(16):1-106.
3. Bailey Jr DB, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008;146A(16):2060-9.
4. Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, et al. Advances in the treatment of fragile X syndrome. Pediatrics. 2009;123(1):378-90.
5. Budimirovic DB, Kaufmann WE. What can we learn about autism from studying fragile X syndrome? Dev Neurosci. 2011;33(5):379-94.
6. Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick Jr RG, Warren ST, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67(6):1047-58.
7. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66(4):817-22.
8. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370-7.
9. Lozano R, Rosero CA, Hagerman RJ. Fragile X spectrum disorders. Intractable Rare Dis Res. 2014;3(4):134-46.
10. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E. Fragile X syndrome: a review of associated medical problems. Pediatrics. 2014;134(5):995-1005.
11. Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008;16(6):666-72.
12. Tsiouris JA, Brown WT. Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. CNS Drugs. 2004;18(11):687-703.
13. Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A. 2004;129A(3):225-34.
14. Budimirovic DB, Bukelis I, Cox C, Gray RM, Tierney E, Kaufmann WE. Autism spectrum disorder in Fragile X syndrome: differential contribution of adaptive socialization and social withdrawal. Am J Med Genet A. 2006;140A(17):1814-26.
15. Gholizadeh S, Halder SK, Hampson DR. Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. Brain Res. 2015;1596:22-30.
16. Weiler IJ, Irwin SA, Klintsova AY, Spencer CM, Brazelton AD, Miyashiro K, Comery TA, Patel B, Eberwine J, Greenugh WT. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci U S A. 1997;94(10):5395-400.
17. Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell. 2008;134(6):1042-54.
18. Corbin F, Bouillon M, Fortin A, Morin S, Rousseau F, Khandjian EW. The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes. Hum Mol Genet. 1997;6(9):1465-72.
19. Feng Y, Absher D, Eberhart DE, Brown V, Malter HE, Warren ST. FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. Mol Cell. 1997;1(1):109-18.
20. Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol. 2012;7:219-45.
21. Sethna F, Moon C, Wang H. From FMRP function to potential therapies for fragile X syndrome. Neurochem Res. 2014;39(6):1016-31.
22. Hazlett HC, Poe MD, Lightbody AA, Styner M, MacFall JR, Reiss AL, Piven J. Trajectories of early brain volume development in fragile X syndrome and autism. J Am Acad Child Adolesc Psychiatry. 2012;51(9):921-33.
23. Rudelli RD, Brown WT, Wisniewski K, Jenkins EC, Laure-Kamionowska M, Connell F, Wisniewski HM. Adult fragile X syndrome. Clinico-neuropathologic findings. Acta Neuropathol. 1985;67(3-4):289-95.
24. Hinton VJ, Brown WT, Wisniewski K, Rudelli RD. Analysis of neocortex in three males with the fragile X syndrome. Am J Med Genet. 1991;41(3):289-94.
25. Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ, Greenough WT. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci U S A. 1997;94(10):5401-4.
26. Huber KM, Gallagher SM, Warren ST, Bear MF. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A. 2002;99(11):7746-50.
27. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron. 2012;76(2):325-37.
28. Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron. 2006;51(4):441-54.
29. Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012;74(1):49-56.
30. Auerbach BD, Bear MF. Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis. J Neurophysiol. 2010;104(2):1047-51.
31. Zhao MG, Toyod H, Ko SW, Ding HK, Wu LJ, Zhuo M. Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J Neurosci. 2005;25(32):7385-92.
32. Yun SH, Trommer BL. Fragile X mice: reduced long-term potentiation and N-methyl-D-aspartate receptor-mediated neurotransmission in dentate gyrus. J Neurosci Res. 2011;89(2):176-82.
33. Martin HG, Lassalle O, Brown JT, Manzoni OJ: Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome. Cereb Cortex. 2016;26(5):2084-92.
34. Gross C, Chang CW, Kelly SM, Bhattacharya A, McBride SM, Danielson SW, Jiang MQ, Chan CB, Ye K, Gibson JR, et al. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep. 2015;11(5):727-36.
35. Gross C, Raj N, Molinaro G, Allen AG, Whyte AJ, Gibson JR, Huber KM, Gourley SL, Bassell GJ. Selective role of the catalytic PI3K subunit p110beta in impaired higher order cognition in fragile X syndrome. Cell Rep. 2015;11(5):681-8.
36. Gross C, Nakamoto M, Yao X, Chan CB, Yim SY, Ye K, Warren ST, Bassell GJ. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci. 2010;30(32):10624-38.
37. Matic K, Eninger T, Bardoni B, Davidovic L, Macek B. Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms. J Proteome Res. 2014;13(10):4388-97.
38. uria G, Gualtieri F, Bartolomeo R, Vezzali R, Biagini G. Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice. Front Cell Neurosci. 2013;7:46.
39. Kim SH, Markham JA, Weiler IJ, Greenough WT. Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome. Proc Natl Acad Sci U S A. 2008;105(11):4429-34.
40. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet. 2009;46(2):94-102.
41. Dansie LE, Phommahaxay K, Okusanya AG, Uwadia J, Huang M, Rotschafer SE, Razak KA, Ethell DW, Ethell IM. Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. Neuroscience. 2013;246:186-98.
42. Qin M, Zeidler Z, Moulton K, Krych L, Xia Z, Smith CB. Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome. Behav Brain Res. 2015;291:164-71.
43. Tang AH, Alger BE. Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome. J Neurosci. 2015;35(9):3938-45.
44. Jung KM, Sepers M, Henstridge CM, Lassalle O, Neuhofer D, Martin H, Ginger M, Frick A, DiPatrizio NV, Mackie K, et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080.
45. Zhang L, Alger BE. Enhanced endocannabinoid signaling elevates neuronal excitability in fragil X syndrome. J Neurosci. 2010;30(16):5724-9.
46. Kim SW, Cho KJ. Activity-dependent alterations in the sensitivity to BDNF-TrkB signaling may promote excessive dendritic arborization and spinogenesis in fragile X syndrome in order to compensate for compromised postsynaptic activity. Med Hypotheses. 2014;83(4):429-35.
47. Castren M, Lampinen KE, Miettinen R, Koponen E, Sipola I, Bakker CE, Oostra BA, Castren E. BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus. Neurobiol Dis. 2002;11(1):221-9.
48. Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS. Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci. 2010;30(2):694-702.
49. Price TJ, Rashid MH, Millecamps M, Sanoja R, Entrena JM, Cervero F. Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci. 2007;27(51):13958-67.
50. Amiri A, Sanchez-Ortiz E, Cho W, Birnbaum SG, Xu J, McKay RM, Parada LF. Analysis of FMR1 deletion in a subpopulation of post-mitotic neurons in mouse cortex and hippocampus. Autism Res. 2014;7(1):60-71.
51. Davenport MH, Schaefer TL, Friedmann KJ, Fitzpatrick SE, Erickson CA. Pharmacotherapy for Fragile X syndrome: progress to date. Drugs. 2016;76(4):431-45.
52. Schaefer TL, Davenport MH, Erickson CA. Emerging pharmacologic treatment options for fragile X syndrome. Appl Clin Genet. 2015;8:75-93.
53. Brown V, Jin P, Ceman S, Darnell JC, O'Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD, et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell. 2001;107(4):477-87.
54. Chuang SC, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RK. Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J Neurosci. 2005;25(35):8048-55.
55. Karachot L, Shirai Y, Vigot R, Yamamori T, Ito M. Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein. J Neurophysiol. 2001;86(1):280-9.
56. Zho WM, You JL, Huang CC, Hsu KS. The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine induces a novel form of depotentiation in the CA1 region of the hippocampus. J Neurosci. 2002;22(20):8838-49.
57. Huber KM, Kayser MS, Bear MF. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science. 2000;288(5469):1254-7.
58. Raymond CR, Thompson VL, Tate WP, Abraham WC. Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation. J Neurosci. 2000;20(3):969-76.
59. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major Fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005;49(7):1053-66.
60. de Vrij FM, Levenga J, van der Linde HC, Koekkoek SK, e Zeeuw CI, Nelson DL, Oostra BA, Willemsen R. Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis. 2008;31(1):127-32.
61. Lindemann L, Jaeschke G, Michalon A, Vieira E, Honer M, Spooren W, Porter R, Hartung T, Kolczewski S, Buttelmann B, et al. CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor. J Pharmacol Exp Ther. 2011;339(2):474-86.
62. Dolen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Correction of fragile X syndrome in mice. Neuron. 2007;56(6):955-62.
63. Thomas AM, Bui N, Graham D, Perkins JR, Yuva-Paylor LA, Paylor R. Genetic reduction of group 1 metabotropic glutamate receptors alters select behaviors in a mouse model for fragile X syndrome. Behav Brain Res. 2011;223(2):310-21.
64. Olmos-Serrano JL, Paluszkiewicz SM, Martin BS, Kaufmann WE, Corbin JG, Huntsman MM. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci. 2010;30(29):9929-38.
65. El Idrissi A, Yan X, L'Amoreaux W, Brown WT, Dobkin C. Neuroendocrine alterations in the fragile X mouse. Results Probl Cell Differ. 2012;54:201-21.
66. D'Hulst C, Heulens I, Brouwer JR, Willemsen R, De Geest N, Reeve SP, De Deyn PP, Hassan BA, Kooy RF. Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain Res. 2009;1253:176-83.
67. D'Hulst C, De Geest N, Reeve SP, Van Dam D, De Deyn PP, Hassan BA, Kooy RF. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 2006;1121(1):238-45.
68. Heulens I, D'Hulst C, Van Dam D, De Deyn PP, Kooy RF. Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model. Behav Brain Res. 2012;229(1):244-9.
69. Chang S, Bray SM, Li Z, Zarnescu DC, He C, Jin P, Warren ST. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat Chem Biol. 2008;4(4):256-63.
70. Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, et al. Reversal of disease-related pathologies in the Fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Transl Med. 2012;4(152):152ra128.
71. Pacey LK, Heximer SP, Hampson DR. Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol Pharmacol. 2009;76(1):18-24.
72. Porter RH, Jaeschke G, Spooren W, Ballard TM, Buttelmann B, Kolczewski S, Peters JU, Prinssen E, Wichmann J, Vieira E, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther. 2005;315(2):711-21.
73. Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet. 2009;46(4):266-71.
74. Friedmann CTH, Davis LJ, Ciccone PE, Rubin RT. Phase-II double-blind controlled-study of a new anxiolytic, fenobam (Mcn-3377) vs placebo. Curr Ther Res Clin E. 1980;27(2):144-51.
75. Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, Ramos FJ, Cornish K, He Y, Paulding C, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3(64):64ra61.
76. Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016;8(321):321ra325.
77. Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D. Psychometric study of the aberrant behavior checklist in fragile x syndrome and implications for targeted treatment. J Autism Dev Disord. 2012;42(7):1377-92.
78. Aman MG, Singh NN, Stewart AW, Field CJ. The Aberrant Behavior Checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;5:485-91.
79. Novartis discontinues development of mavoglurant (AFQ056) for Fragile X syndrome. http://www.fraxa.org/novartis-discontinues-development-mavoglurant-afq056-fragile-x-syndrome/.
80. Roche Letter. http://www.fiercebiotech.com/r-d/roche-abandons-another-fragile-x-r-d-program-after-phii-trials-flunk-out.
81. Hu H, Qin Y, Bochorishvili G, Zhu Y, van Aelst L, Zhu JJ. Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J Neurosci. 2008;28(31):7847-62.
82. Pilpel Y, Kolleker A, Berberich S, Ginger M, Frick A, Mientjes E, Oostra BA, Seeburg PH. Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice. J Physiol. 2009;587(Pt 4):787-804.
83. Eadie BD, Cushman J, Kannangara TS, Fanselow MS, Christie BR. NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus. 2012;22(2):241-54.
84. Erickson CA, Mullett JE, McDougle CJ. Open-label memantine in fragile X syndrome. J Autism Dev Disord. 2009;39(12):1629-35.
85. Berry-Kravis E, Krause SE, Block SS, Guter S, Wuu J, Leurgans S, Decle P, Potanos K, Cook E, Salt J, et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol. 2006;16(5):525-40.
86. Gallagher SM, Daly CA, Bear MF, Huber KM. Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1. J Neurosci. 2004;24(20):4859-64.
87. Wang X, Snape M, Klann E, Stone JG, Singh A, Petersen RB, Castellani RJ, Casadesus G, Smith MA, Zhu X. Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome. J Neurochem. 2012;121(4):672-9.
88. Osterweil EK, Krueger DD, Reinhold K, Bear MF. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippcampus of a mouse model of fragile X syndrome. J Neurosci. 2010;30(46):15616-27.
89. Zarate Jr CA, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004;161(1):171-4.
90. Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2007;17(6):761-7.
91. Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 1993;250(3):473-6.
92. Jahn K, Schlesinger F, Jin LJ, Dengler R, Bufler J, Krampfl K. Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABA(A)-receptors. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(1):53-63.
93. Erickson CA, Weng N, Weiler IJ, Greenough WT, Stigler KA, Wink LK, McDougle CJ. Open-label riluzole in fragile X syndrome. Brain Res. 2011;1380:264-70.
94. Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries FE, Lambers FA, Hatia F, et al. Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci U S A. 2004;101(50):17504-9.
95. Boismare F, Daoust M, Moore N, Saligaut C, Lhuintre JP, Chretien P, Durlach J. A homotaurine derivative reduces the voluntary intake of ethano by rats: are cerebral GABA receptors involved? Pharmacol Biochem Behav. 1984;21(5):787-9.
96. Harris BR, Prendergast MA, Gibson DA, Rogers DT, Blanchard JA, Holley RC, Fu MC, Hart SR, Pedigo NW, Littleton JM. Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcohol Clin Exp Res. 2002;26(12):1779-93.
97. Mann K, Kiefer F, Spanagel R, Littleton J. Acamprosate: recent findings and future research directions. Alcohol Clin Exp Res. 2008;32(7):1105-10.
98. Erickson CA, Mullett JE, McDougle CJ. Brief report: acamprosate in fragile X syndrome. J Autism Dev Disord. 2010;40(11):1412-6.
99. Erickson CA, Wink LK, Ray B, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, Lahiri DK, McDougle CJ. Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl). 2013;228(1):75-84.
100. Erickson C, Ray B, Maloney B, Wink LK, Bowers K, Schaefer TL, McDougle C, Sokol DK, Lahiri D: Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. J. Psychiatr. Res 2014, in press.
101. Braat S, D'Hulst C, Heulens I, De Rubeis S, Mientjes E, Nelson DL, Willemsen R, Bagni C, Van Dam D, De Deyn PP, et al. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell Cycle. 2015;14(18):2985-95.
102. Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, et al. Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Sci Transl Med. 2012;4(152):152ra127.
103. Fornai F, Grazia Alessandri M, Bonuccelli U, Scalori V, Corsini GU. Effect of metadoxine on striatal dopamine levels in C57 black mice. J Pharm Pharmacol. 1993;45(5):476-8.
104. Alcobra announces results from phase 2 clinical trial of MDX for fragile X syndrome. http://www.alcobra-pharma.com/releasedetail.cfm?ReleaseID=919218.
105. Bailey Jr DB, Berry-Kravis E, Wheeler A, Raspa M, Merrien F, Ricart J, Koumaras B, Rosenkranz G, Tomlinson M, von Raison F, et al. Mavoglurant in adolescents with fragile X syndrome: analysis of Clinical Global Impression-Improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J Neurodev Disord. 2016;8:1.
106. Jope RS, Roh MS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets. 2006;7(11):1421-34.
107. Portis S, Giunta B, Obregon D, Tan J. The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome. Int J Physiol Pathophysiol Pharmacol. 2012;4(3):140-8.
108. Liu ZH, Chuang DM, Smith CB. Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome. Int J Neuropsychopharmacol. 2011;14(5):618-30.
109. Liu ZH, Huang T, Smith CB. Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome Neurobiol Dis. 2012;45(3):1145-52.
110. Choi CH, Schoenfeld BP, Bell AJ, Hinchey P, Kollaros M, Gertner MJ, Woo NH, Tranfaglia MR, Bear MF, Zukin RS, et al. Pharmacological reversal of synaptic plasticity deficits in the mouse model of Fragile X syndrome by group II mGluR antagonist or lithium treatment. Brain Res. 2011;1380:106-19.
111. Yuskaitis CJ, Mines MA, King MK, Sweatt JD, Miller CA, Jope RS. Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome. Biochem Pharmacol. 2010;79(4):632-46.
112. Franklin AV, King MK, Palomo V, Martinez A, McMahon LL, Jope RS. Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice. Biol Psychiatry. 2014;75(3):198-206.
113. Berry-Kravis E, Sumis A, Hervey C, Nelson M, Porges SW, Weng N, Weiler IJ, Greenough WT. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr. 2008;29(4):293-302.
114. Bilousova TV, Rusakov DA, Ethell DW, Ethell IM. Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem. 2006;97(1):44-56.
115. Bilousova T, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM: Minocycline promotes dendritic spine maturation and improves behavioral performance in the fragile X mouse model. J Med Genet. 2009;46(2):94-102.
116. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, Ethell DW. Open-label add-on treatment trial of minocycline in fragile X syndome. BMC Neurol. 2010;10:91.
117. Leigh MJ, Nguyen DV, Mu Y, Winarni TI, Schneider A, Chechi T, Polussa J, Doucet P, Tassone F, Rivera SM, et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr. 2013;34(3):147-55.
118. Schneider A, Leigh MJ, Adams P, Nanakul R, Chechi T, Olichney J, Hagerman R, Hessl D. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol. 2013;27(10):956-63.
119. Dziembowska M, Pretto DI, Janusz A, Kaczmarek L, Leigh MJ, Gabriel N, Durbin-Johnson B, Hagerman RJ, Tassone F. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013;161(8):1897-903.
120. Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, et al. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218(2):272-80.
121. Cerezo-Guisado MI, Garcia-Roman N, Garcia-Marin LJ, Alvarez-Barrientos A, Bragado MJ, Lorenzo MJ. Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts. Biochem J. 2007;401(1):175-83.
122. Xu XQ, McGuire TF, Blaskovich MA, Sebti SM, Romero G. Lovastatin inhibits the stimulation of mitogen-activated protein kinase by insulin in HIRcB fibroblasts. Arch Biochem Biophys. 1996;326(2):233-7.
123. Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RK, Bear MF. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron. 2013;77(2):243-50.
124. Caku A, Pellerin D, Bouvier P, Riou E, Corbin F. Effect of lovastatin on behavior in children and adults with fragile X syndrome: an open-label study. Am J Med Genet A. 2014;164A(11):2834-42.
125. Berry-Kravis E, Levin R, Shah H, Mathur S, Darnell JC, Ouyang B. Cholesterol levels in fragile X syndrome. Am J Med Genet A. 2015;167A(2):379-84.
126. Cartagena CM, Phillips KL, Williams GL, Konopko M, Tortella FC, Dave JR, Schmid KE. Mechanism of action for NNZ-2566 anti-inflammatory effects following PBBI involves upregulation of immunomodulator ATF3. Neuromolecular Med. 2013;15(3):504-14.
127. Wei HH, Lu XC, Shear DA, Waghray A, Yao C, Tortella FC, Dave JR. NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats. J Neuroinflammation. 2009;6:19.
128. Lu XC, Chen RW, Yao C, Wei H, Yang X, Liao Z, Dave JR, Tortella FC. NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury. J Neurotrauma. 2009;26(1):141-54.
129. Deacon RM, Glass L, Snape M, Hurley MJ, Altimiras FJ, Biekofsky RR, Cogram P. NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragil X syndrome. Neuromolecular Med. 2015;17(1):71-82.
130. Abitbol M, Menini C, Delezoide AL, Rhyner T, Vekemans M, Mallet J. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nat Genet. 1993;4(2):147-53.
131. Kesler SR, Lightbody AA, Reiss AL. Cholinergic dysfunction in fragile X syndrome and potential intervention: a preliminary 1H MRS study. Am J Med Genet A. 2009;149A(3):403-7.
132. D'Antuono M, Merlo D, Avoli M. Involvement of cholinergic and gabaergic systems in the fragile X knockout mice. Neuroscience. 2003;119(1):9-13.
133. Sahu JK, Gulati S, Sapra S, Arya R, Chauhan S, Chowdhury MR, Gupta N, Kabra M, Gupta YK, Dwivedi SN, et al. Effectiveness and safety of donepezil in boys with fragile x syndrome: a double-blind, randomized, controlled pilot study. J Child Neurol. 2013;28(5):570-5.
134. Chugani DC, Muzik O, Chakraborty P, Mangner T, Chugani HT. Human brain serotonin synthesis capacity measured in vivo with a-(C-11) methyl-L-tryptophan. Synapse-New York. 1998;28:33-43.
135. Hanson AC, Hagerman RJ. Serotonin dysregulation in fragile X syndrome: Implications for treatment. Intractable Rare Dis Res. 2014;3(4):110-7.
136. Jeste SS, Geschwind DH. Clinical trials for neurodevelopmental disorders: at a therapeutic frontier. Sci Transl Med. 2016;8(321):321fs321.
137. Budimirovic D, Duy P. Challenges in translating therapeutic frontiers in clinical trials: where are we now and what's next. Madridge J Neuro Sci. 2016;1(1):e1-3.
138. McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314-21.
139. Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH, Aman MG. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2009;48(11):1110-9.
140. Kaufmann WE, Capone GT, Clarke M, Budimirovic DB: Autism in genetic intellectual disability. In: Autism. Springer; 2008:81-108. http://www.springer.com/us/book/9781603274883.
141. Wolff JJ, Bodfish JW, Hazlett HC, Lightbody AA, Reiss AL, Piven J. Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism. J Am Acad Child Adolesc Psychiatry. 2012;51(12):1324-32.
142. Ethridge L, White S, Mosconi M, Wang J, Byerly M, Sweeney J. Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome. Transl Psychiatry. 2016;6(4), e787.
143. Hall SS, Lightbody AA, McCarthy BE, Parker KJ, Reiss AL. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology. 2012;37(4):509-18.