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Four articles in this issue of the Journal describe various steps in the cascade of research from gene discovery to potential treatment in fragile X syndrome (FXS) [1–4]. Objectively, FXS is one of the most productive areas of research in neurodevelopmental disorders. Twenty-six years ago, the cause of FXS was identified as a trinucleotide repeat expansion that disrupts FMR1 gene expression [5]. This discovery quickly led to cellular and mouse models that lacked the corresponding protein, FMRP, leading in turn to fundamental insights into its function in the cell and at the synapse. Over the past 12 years, several groups have identified small molecules that rescue neuroanatomical, electrophysiological, and behavioral features in animal models of FXS. These results are tremendously exciting! Subjectively, it has been harder to maintain an appropriate level of excitement. Based upon results in mouse models [6, 7], three pharmaceutical companies stepped up to test novel compounds in well-powered controlled trials in FXS. A couple of early pilot studies raised hopes further. Unfortunately, larger follow-up studies showed no significant findings in adults or adolescents with fragile X syndrome, including one study published in this issue of the Journal [2]. As a result, one of the three companies folded and the other two pulled out of FXS research. We should not have expected that it would be simple to translate findings from a rodent model of FXS into humans. Clearly, the pharmaceutical industry has had tremendous success translating molecular findings in other areas, like breast cancer or HIV. Unfortunately, however, there are no examples of successful drug development programs in neurodevelopmental disorders that would indicate how best to test a potential drug for FXS. To draw on a sports analogy, this would be like a professional golfer picking up a baseball bat and expecting to hit a home run on his first at-bat. The initial programs for these three compounds were three swings to hit the ball over the fence. None of the programs hit a home run. The good news is that baseball games are not determined by the first at-bat. The four articles in this issue offer us perspectives on the challenges and potential rewards of the translational game. One of these challenges is deciphering what model systems are telling us in relation to the human disorder. In this issue, Schaefer and colleagues [1] describe studies of acamprosate, which is approved by the Food and Drug Administration (FDA) for maintenance treatment of alcohol dependence. Acamprosate is not a simple drug. It binds to glutamatergic NMDA receptors and also seems to have mGluR5 and GABA-A effects. Likewise, the Fmr1 null mouse is not a simple model. The authors use a different inbred mouse strain than in much of the literature and find no change in dendritic spine density in the Fmr1 null compared to wildtype controls, despite this phenotype being a common target of rescue experiments on other inbred strain backgrounds. They do find an increase in synchronous neuronal firing in the somatosensory cortex, which is normalized by acamprosate. Likewise, they find that this drug rescues changes in ERK signaling and activity levels. These are important findings, but one of the key challenges in translating findings from mouse to human has been the lack of straightforward cognitive (or social) deficits in the Fmr1 null mouse. Another challenge to translational research in FXS has been that the first three large-scale clinical trial programs studied adolescents and adults, rather than aiming to treat this neurodevelopmental disorder during childhood. In this issue, Berry-Kravis and colleagues describe two randomized, placebo-controlled trials of arbaclofen [2], a GABA-B agonist, that follow up suggestive findings in a phase 2 randomized, cross-over study [8]. The results of the larger study, a two-group trial of one dose versus placebo in adults and adolescents (n = 125), parallel the negative findings in trials of mGluR5 negative allosteric modulators in adults and adolescents [9]. Correspondence: veenstr@nyspi.columbia.edu Department of Psychiatry and Sackler Institute of Developmental Psychobiology, Columbia University, New York, NY, USA New York State Psychiatric Institute, New York, NY, USA Full list of author information is available at the end of the article

Translation in fragile X: no home runs in the first at-bat