Review of Salient Investigational Drugs for the Treatment of Fragile X Syndrome

Objectives: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, in addition to being the commonest diagnosable cause of autism. The identification of the biochemical mechanism underlying this disorder has provided amenable targets for therapy. This review aims to provide an overview of investigational drug therapies for FXS.

Methods: The authors carried out a search of clinical and preclinical trials for FXS in PubMed and on the U.S. National Institutes of Health index of clinical trials ( www.clinicaltrials.gov ). We limited our review to Phase II trials or more preliminary and reviewed the associated publications for these studies, complemented by a review of the literature on PubMed.

Results: The review of the preclinical, Phase I, and Phase II trials of agents with therapeutic potential in FXS revolves around an understanding of the putative pathways in the pathogenesis of FXS. While there is significant overlap between some of these pathways, the agents can be categorized as modulators of the metabotropic glutamate receptor system, GABAergic agents, and miscellaneous modulators affecting other pathways.

Conclusion: As trials involving agents targeting different aspects of the molecular biology proceed, common themes have emerged. With the great hope came great disappointment as the initial trials failed to demonstrate sufficient significance. In particular, the differences in outcome between the animal models and humans have highlighted the unique challenges of carrying out trials in these cognitively and behaviorally challenged individuals, as well as a dearth of clinically relevant outcome measures for use in medication trials. However, in reviewing and reframing the studies of the last decade, many important lessons have been learned, which will ultimately have a greater impact on therapeutic research in the field of developmental delay as a whole.