Progress and Struggles in Translating Scientific Advances into Human Therapy

Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most frequent single gene cause of autism, affecting 1 in 5,000 males and a lesser number of females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. The Fragile X gene (FMR1) was cloned in 1991 and since then a large field has grown with more than a hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMRP is primarily a polyribosome-associated protein that regulates the translation of a set of messages highly enriched for synaptic proteins. In addition to regulating translation in the cell body FMRP has been found to interact with and accompany a crucial subset of messages to the sites of neural communication (the synapses). At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity, causing synapses to strengthen or weaken in response to experience. Specific signaling mechanisms have been proposed to mediate this control at the synapse, including group I metabotropic glutamate receptors. In addition, a great deal has been discovered about the effects of loss of FMRP function on dendritic spine dynamics, and altered synaptic transmission in various brain areas, and understanding has been extended to the impact of altered synaptic responses on circuit function and learning in model organisms. Functions for FMRP other than its role as a translational regulator have also recently come to light. Generalizing these findings to human patients suggests that when FMRP is missing synapses are less able to change with experience and learning is greatly reduced.

It has become clear that in addition to the clinical overlap between FXS and autism spectrum disorders (ASD), there is likely substantial overlap in the molecular pathology of the two disorders. As such, molecular defects known to cause ASD and other neurodevelopmental disorders (NDD) may involve other proteins in the signaling pathways that are regulated by or regulate FMRP activity, may involve proteins whose translation is regulated by FMRP, or may involve defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in such pathways are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies for patients with FXS. It is expected that many of these targeted treatments will have therapeutic overlap in subsets of individuals with ASD or NDD.

This conference will bring together leading scientists and clinicians in the Fragile X, ASD, and NDD fields, particularly those working on forms of ASD/NDD with dysfunctions in molecular pathways that overlap those implicated in FXS. Topics will include the latest developments in genetics of ASDs and related diseases, FMRP function and its regulation, the overlap between the diseases at the molecular and genetic level, model system characterizations, dendritic spine dynamics and synaptic plasticity studies, outcome measures, and translation to treatment trials in humans with FXS and ASD/NDD. The conference is expected to accelerate the pace of bench-to-bedside translational research to bring important targeted treatments to individuals with FXS and ASD-related disorders.