Fragile X Syndrome : the quest for targeted treatment

Fragile X syndrome is the most common hereditary cause of intellectual disability and autism. Currently, no targeted treatment is available. The identification of its causative gene, followed by the generation of animal models, has boosted research options. The past decades, preclinical research has focused on involved pathways as targets for therapeutic interventions. Targeting many of these pathways in animal models improved core features of the disease. These promising results were received with great enthusiasm, and led to clinical trials in patients with fragile X syndrome. The aim of this thesis was to develop and evaluate therapeutic intervention strategies for fragile X syndrome with the ultimate goal to advance care and treatment options for patients with the disorder. One aspect was to identify possible targets for therapeutic intervention using social behavior of Fmr1 knockout mice as outcome measure. In addition, new strategies were explored using combination therapy (chapter one - four). A second aspect was to investigate a potential target, the mGluR5, for its efficacy in clinical trials. The mGluR5 antagonist mavoglurant was studied in a multicenter randomized, double-blind, placebo-controlled trial (chapter five). A third aspect was to center patient care, in order to advance clinical expertise and enable clinical research. An expert center and clinical guidelines are indispensable in patient care and further development of treatment for fragile X syndrome (chapter seven). The findings were then placed in the light of current knowledge and future prospectives (chapter six and eight).