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Targeted Treatments in Fragile X Syndrome

Saturday, 4 May 2013: 12:00
Auditorium (Kursaal Centre)
S. Jacquemont1, A. Curie2, V. des Portes3, M. G. Torrioli4, E. Berry-Kravis5, R. Hagerman6, F. J. Ramos7, K. Cornish8, Y. He9, C. Paulding9, G. Neri10, F. Gasparini11, A. Floesser12, J. Branson11, G. Bilbe11, D. Johns13 and B. Gomez-Mancilla13, (1)Medical Genetics, University Hospital of Lausanne, University of Lausanne, Lausanne, Switzerland, (2)Hospices Civils de Lyon, Université de Lyon and CNRS, Lyon, France, (3)Hospices Civils de Lyon, Université de Lyon and CNRS UMR 5230 (L2C2), Lyon, France, (4)Università Cattolica del Sacro Cuore, Cattedra di Neuropsichiatria Infantile, Rome, Italy, (5)Rush University Medical Center, Chicago, IL, (6)Fragile X Research and Treatment Center, UC Davis MIND Institute, Sacramento, CA, (7)Department of Pediatrics, University of Zaragoza Medical School,, Zaragoza, Spain, (8)School of Psychology, Psychiatry, & Psychological Medicine, Victoria, Australia, (9)Biomarker Development, Novartis Institutes for Biomedical Research, Cambridge, MA, (10)Università Cattolica del Sacro Cuore, Istituto di Genetica Medica, Rome, Italy, (11)Neuroscience Discovery, Novartis Pharma AG, Basel, Switzerland, (12)Neuroscience Clinical Sciences and Innovation, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland, (13)Neuroscience Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
Fragile X syndrome (FXS) is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and subsequent transcriptional silencing. The absence of FMRP (FMR1 protein) at the synapse has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. It has been postulated that this increased mGluR5 signal may be responsible for many of the clinical manifestations observed in fragile X syndrome. mGluR5 receptor antagonists have repeatedly been shown to rescue many phenotypes and endophenotypes in animal models of the fragile X syndrome. Comprehensive phenotype correction also occurs when treatment is administered later in the adult KO mice. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however the patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.
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