The challenges of clinical trials in fragile X syndrome

Psychopharmacology

Volumn 231, Issue 6, 2014, Pages 1237-1250

  Jacquemont, Sébastien ^a   Berry Kravis, Elizabeth ^b   Hagerman, Randi ^c   Von Raison, Florian ^d   Gasparini, Fabrizio ^d   Apostol, George ^d   Ufer, Mike ^d   Des Portes, Vincent ^e   Gomez Mancilla, Baltazar ^d  

^a LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

^b RUSH UNIVERSITY MEDICAL CENTER   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d NOVARTIS PHARMA AG   (Switzerland)

^e UNIVERSITÉ DE LYON   (France)

Author keywords

AFQ056; Arbaclofen; Autism spectrum disorder; Disease modification; FMR1; FMRP; Fragile X syndrome; GABA; Mavoglurant; mGluR5

Indexed keywords

ACAMPROSATE; AF Q056; ARBACLOFEN; ARIPIPRAZOLE; FENOBAM; FRAGILE X MENTAL RETARDATION PROTEIN; GANAXOLONE; LITHIUM; MAVOGLURANT; MEMANTINE; METABOTROPIC RECEPTOR ANTAGONIST; MINOCYCLINE; NPL 2009; RG 7090; RO 4917523; SERTRALINE; STX 107; UNCLASSIFIED DRUG;

AUTISM; BEHAVIOR DISORDER; CLINICAL RESEARCH; COGNITIVE DEFECT; DISEASE ASSOCIATION; DRUG EFFICACY; FMR1 GENE; FRAGILE X SYNDROME; GENETIC HETEROGENEITY; HUMAN; OPEN STUDY; OUTCOME ASSESSMENT; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPIC VARIATION; POST HOC ANALYSIS; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; REVIEW; STRATIFIED SAMPLE;

ANIMALS; CHILD DEVELOPMENT DISORDERS, PERVASIVE; CLINICAL TRIALS AS TOPIC; FRAGILE X SYNDROME; HUMANS; PHENOTYPE;

EID: 84896723006     PISSN: 00333158     EISSN: 14322072     Source Type: Journal    
DOI: 10.1007/s00213-013-3289-0     Document Type: Review

References (72)

1. Aman MG, Singh NN, Stewart AW, Field CJ (1985) The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 89:485-491 (Pubitemid 15104762)
2. Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T (2012) FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492:382-386
3. Auerbach BD, Osterweil EK, Bear MF (2011) Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480:63-68
4. Bardoni B, Mandel JL (2002) Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr Opin Genet Dev 12:284-293 (Pubitemid 34663761)
5. Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL (2011) Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J Neurosci 31:8862-8869
6. Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370-377 (Pubitemid 38829251)
7. Bell MV, Hirst MC, Nakahori Y, MacKinnon RN, Roche A, Flint TJ, Jacobs PA, Tommerup N, Tranebjaerg L, Froster-Iskenius U (1991) Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64:861-866 (Pubitemid 121001172)
8. Berry-Kravis E, Sumis A, Hervey C, Nelson M, Porges SW, Weng N, Weiler IJ, Greenough WT (2008) Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr 29:293-302
9. Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266-271
10. Berry-Kravis E, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RJ (2012) Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 4:152ra127
11. Berry-Kravis E, Hessl D, Abbeduto L, Reiss AL, Beckel-Mitchener A, Urv TK, Outcome measures working groups (2013) Outcome measures for clinical trials in fragile X syndrome. J Dev Behav Pediatr 34:508-522
12. Bilousova TV, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM (2009) Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 46:94-102
13. Choi CH, McBride SM, Schoenfeld BP, Liebelt DA, Ferreiro D, Ferrick NJ, Hinchey P, Kollaros M, Rudominer RL, Terlizzi AM, Koenigsberg E, Wang Y, Sumida A, Nguyen HT, Bell AJ, McDonald TV, Jongens TA (2010) Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue. Biogerontology 11:347-362
14. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W (2003) Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview - revised. J Autism Dev Disord 33:427-433 (Pubitemid 37127938)
15. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247-261
16. de Vries BB, Wiegers AM, Smits AP, Mohkamsing S, Duivenvoorden HJ, Fryns JP, Curfs LM, Halley DJ, Oostra BA, van den Ouweland AM, NiermeijerMF (1996)Mental status of females with an FMR1 gene full mutation. Am J Hum Genet 58:1025-1032 (Pubitemid 26115174)
17. de Vrij FM, Levenga J, van der Linde HC, Koekkoek SK, De Zeeuw CI, Nelson DL, Oostra BA, Willemsen R (2008) Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis 31:127-132 (Pubitemid 351822560)
18. D'Hulst C, Kooy RF (2007) The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci 30:425-431 (Pubitemid 47088715)
19. Dyer-Friedman J, Glaser B, Hessl D, Johnston C, Huffman LC, Taylor A, Wisbeck J, Reiss AL (2002) Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. J Am Acad Child Adolesc Psychiatry 41:237-244 (Pubitemid 38338144)
20. El Fatimy R, Tremblay S, Dury AY, Solomon S, De Koninck P, Schrader JW, Khandjian EW (2012) Fragile X mental retardation protein interacts with the RNA-binding protein Caprin1 in neuronal RiboNucleoProtein complexes [corrected]. PLoS One 7:e39338
21. Erickson CA, Mullett JE, McDougle CJ (2009) Open-label memantine in fragile X syndrome. J Autism Dev Disord 39:1629-1635
22. Erickson CA, Mullett JE, McDougle CJ (2010) Brief report: acamprosate in fragile X syndrome. J Autism Dev Disord 40:1412-1416
23. Erickson CA, Stigler KA, Wink LK, Mullett JE, Kohn A, Posey DJ, McDougle CJ (2011) A prospective open-label study of aripiprazole in fragile X syndrome. Psychopharmacology 216:85-90
24. Erickson CA, Wink LK, Ray B, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, Lahiri DK, McDougle CJ (2013) Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl) 228:75-84
25. Facco E, Zanette G, Favero L, Bacci C, Sivolella S, Cavallin F, Manani G (2011) Toward the validation of visual analogue scale for anxiety. Anesth Prog 58:8-13
26. Fatemi SH, Folsom TD (2011) Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism 2:6
27. Fatemi SH, Reutiman TJ, Folsom TD, Rooney RJ, Patel DH, Thuras PD (2010) mRNA and protein levels for GABAAalpha4, alpha5, beta1 and GABABR1 receptors are altered in brains from subjects with autism. J Autism Dev Disord 40:743-750
28. Fatemi SH, Folsom TD, Kneeland RE, Liesch SB (2011) Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both fragile X mental retardation protein and GABAA receptor beta 3 in adults with autism. Anat Rec (Hoboken) 294:1635-1645
29. Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16:666-672 (Pubitemid 351753362)
30. Gross C, Berry-Kravis EM, Bassell GJ (2012) Therapeutic strategies in fragile X syndrome: dysregulated mGluR signaling and beyond. Neuropsychopharmacology 37:178-195
31. Hagerman RJ, Hagerman PJ (2002) Fragile X syndrome: diagnosis, treatment and research. Johns Hopkins University Press, Baltimore
32. Hagerman RJ, Hull CE, Safanda JF, Carpenter I, Staley LW, O'Connor RA, Seydel C, Mazzocco MM, Snow K, Thibodeau SN (1994) High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet 51:298-308 (Pubitemid 24197696)
33. Hagerman R, Hoem G, Hagerman P (2010) Fragile X and autism: intertwined at the molecular level leading to targeted treatments. Mol Autism 1:12
34. Hall SS, Lightbody AA, Reiss AL (2008) Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome. Am J Ment Retard 113:44-53
35. Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barbato I, Tassone F, Hagerman PJ, Herman H, Hagerman RJ (2008) Autism profiles of males with fragile X syndrome. Am J Ment Retard 113: 427-438
36. Hessl D, Dyer-Friedman J, Glaser B, Wisbeck J, Barajas RG, Taylor A, Reiss AL (2001) The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome. Pediatrics 108:E88
37. Hessl D, Nguyen DV, Green C, Chavez A, Tassone F, Hagerman RJ, Senturk D, Schneider A, Lightbody A, Reiss AL, Hall S (2009) A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J Neurodev Disord 1:33-45
38. Indah Winarni T, Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, Nguyen DV, Hagerman RJ (2012) Sertraline may improve language developmental trajectory in young children with fragile X syndrome: a retrospective chart review. Autism Res Treat 2012:104317
39. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285-299
40. Iwahashi C, Tassone F, Hagerman RJ, Yasui D, Parrott G, Nguyen D, Mayeur G, Hagerman PJ (2009) A quantitative ELISA assay for the fragile X mental retardation 1 protein. J Mol Diagn 11:281-289
41. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA (2007) Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 6:45-55 (Pubitemid 44880272)
42. Jacquemont S, Curie A, Des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, Ramos FJ, Cornish K, He Y, Paulding C, Neri G, Chen F, Hadjikhani N, Martinet D, Meyer J, Beckmann JS, Delange K, Brun A, Bussy G, Gasparini F, Hilse T, Floesser A, Branson J, Bilbe G, Johns D, Gomez-Mancilla B (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra1
43. Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P (2004) Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A 129A:225-234 (Pubitemid 39166187)
44. Knox A, Schneider A, Abucayan F, Hervey C, Tran C, Hessl D, Berry-Kravis E (2012) Feasibility, reliability, and clinical validity of the Test of Attentional Performance for Children (KiTAP) in fragile X syndrome (FXS). J Neurodev Disord 4:2
45. Lam KS, Aman MG (2007) The Repetitive Behavior Scale - Revised: independent validation in individuals with autism spectrum disorders. J Autism Dev Disord 37:855-866 (Pubitemid 46790783)
46. Leigh MJS, Nguyen DV, Mu Y, Winarni TI, Schneider A, Chechi T, Polussa J, Doucet P, Tassone F, Rivera SM, Hessl D, Hagerman RJ (2013) A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile X syndrome. J Dev Behav Pediatr 34:147-155
47. Levenga J, de Vrij FM, Oostra BA, Willemsen R (2010) Potential therapeutic interventions for fragile X syndrome. Trends Mol Med 16:516-527
48. Levenga J, Hayashi S, de Vrij FM, Koekkoek SK, van der Linde HC, Nieuwenhuizen I, Song C, Buijsen RA, Pop AS, Gomezmancilla B, Nelson DL, Willemsen R, Gasparini F, Oostra BA (2011) AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol Dis 42:311-317
49. Loesch DZ, Huggins RM, Hagerman RJ (2004) Phenotypic variation and FMRP levels in fragile X.Ment Retard Dev Disabil Res Rev 10:31-41 (Pubitemid 38375351)
50. McBride SM, Choi CH, Wang Y, Liebelt D, Braunstein E, Ferreiro D, Sehgal A, Siwicki KK, Dockendorff TC, Nguyen HT, McDonald TV, Jongens TA (2005) Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroombody defects in a Drosophila model of fragile X syndrome. Neuron 45:753-764 (Pubitemid 40320709)
51. McLennan Y, Polussa J, Tassone F, Hagerman R (2011) Fragile X syndrome. Curr Genomics 12:216-224
52. Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L (2012) Chronic pharmacological mGlu5 inhibition corrects fragile Xin adultmice. Neuron 74:49-56
53. National Institute of Mental Health (1970) CGI: clinical global impressions. In: Guy W, Bonato RR (eds) Manual of the ECDEU assessment battery. National Institute of Mental Health, Rockville
54. Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B, Hagerman RJ (2007) The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr 28:133-138 (Pubitemid 46624838)
55. Orlova KA, Crino PB (2010) The tuberous sclerosis complex. Ann N Y Acad Sci 1184:87-105
56. Paribello C, Tao L, Folino A, Berry-Kravis E, Tranfaglia M, Ethell IM, Ethell DW (2010) Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol 10:91
57. Reiss AL, Freund LS, Baumgardner TL, Abrams MT, Denckla MB (1995) Contribution of the FMR1 gene mutation to human intellectual dysfunction. Nat Genet 11:331-334
58. Rogers SJ, Wehner DE, Hagerman R (2001) The behavioral phenotype in fragile X: symptoms of autismin very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr 22:409-417 (Pubitemid 34026944)
59. Rogers TD, McKimm E, Dickson PE, Goldowitz D, Blaha CD, Mittleman G (2013) Is autism a disease of the cerebellum? An integration of clinical and pre-clinical research. Front Syst Neurosci 7:15
60. Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D (2012) Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment. J Autism Dev Disord 42:1377-1392
61. Schenck A, Bardoni B, Langmann C, Harden N, Mandel JL, Giangrande A (2003) CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 38:887-898 (Pubitemid 36782381)
62. Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS (2010) Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 30:694-702
63. Sparrow S, Balla D, Cicchetti D (1984) Vineland adaptive behavior scales: interview edition. American Guidance Service, Circle Pines
64. Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, Warren ST (1992) DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1:397-400
65. Tassone F, Hagerman RJ, Ikle DN, Dyer PN, Lampe M, Willemsen R, Oostra BA, Taylor AK (1999) FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet 84: 250-261 (Pubitemid 29206978)
66. Tucker B, Richards RI, Lardelli M (2006) Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. Hum Mol Genet 15:3446-3458 (Pubitemid 44811597)
67. Utari A, Chonchaiya W, Rivera SM, Schneider A, Hagerman RJ, Faradz SM, Ethell IM, Nguyen DV (2010) Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am J Intellect Dev Disabil 115:433-443
68. Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, Zhao MG, Zhuo M (2008) FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron 59: 634-647
69. Willemsen R, Mohkamsing S, de Vries B, Devys D, van den Ouweland A, Mandel JL, Galjaard H, Oostra B (1995) Rapid antibody test for fragile X syndrome. Lancet 345:1147-1148
70. Willemsen R, Smits A, Mohkamsing S, van Beerendonk H, de Haan A, de Vries B, van den Ouweland A, Sistermans E, Galjaard H, Oostra BA (1997) Rapid antibody test for diagnosing fragile X syndrome: a validation of the technique. Hum Genet 99:308-311 (Pubitemid 27095789)
71. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053-1066 (Pubitemid 41503304)
72. Zarnescu DC, Shan G,Warren ST, Jin P (2005) Come FLY with us: toward understanding fragile X syndrome. Genes Brain Behav 4:385-392 (Pubitemid 41192449)