The Search for an Effective Therapy to Treat Fragile X Syndrome: Dream or Reality?

Abstract

Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 (FMR1) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies have found a large number of FMRP mRNA targets, but it is still not clear which are those playing a critical role in the etiology of FXS. So far, no therapy for FXS has been found, making the quest for novel targets of considerable importance. Several pharmacological approaches have been attempted, but, despite some promising preclinical results, no strategy gave successful outcomes, due either to the induction of major side effects or to the lack of improvement of the phenotypes. However, these studies suggested that, in order to measure the effectiveness of a specific treatment, trials should be redesigned and new endpoints defined in FXS patients. Nevertheless, the search for new therapeutic targets for FXS is very active. In this context, the advances in animal modeling, coupled with better understanding of neurobiology and physiopathology of FXS, are of crucial importance in developing new selected treatments. Here, we discuss the pathways that were recently linked to the physiopathology of FXS (mGluR, GABAR, insulin, Insulin-like Growth Factor 1 (IGF-1), MPP-9, serotonin, oxytocin and endocannabinoid signaling) and that suggest new approaches to find an effective therapy for this disorder. Our goal with this review article is to summarize some recent relevant findings on FXS treatment strategies in order to have a clearer view of the different pathways analyzed to date emphasizing those shared with other synaptic disorders.

HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein

“…Current clinical approaches are focused on behavioral therapy and off-label medications that only mitigate a limited set of symptoms, such as hyperactivity, seizures or anxiety ( 4 ). Recent clinical trials based on antagonist of metabotropic glutamate Receptor 5 (mGlu5) and antagonist of GABA-B receptor were discontinued ( 5 , 6 ). The understanding of the physiopathology of FXS and the development of a specific therapy are intimately linked to the understanding of FMRP function and then to the identification of FMRP mRNA targets.…”

Repeat expansion and methylation-sensitive triplet-primed polymerase chain reaction for fragile X mental retardation 1 gene screening in institutionalised intellectually disabled individuals

“…Insulin and insulin-like growth factor pathway, serotonin pathway and endocannabinoid pathway are some of the therapeutic targets in which preclinical Page 11 of 16 trials have obtained promising results. (18) The increased diagnostic rates in FXS need to be coexistent with the development of new treatments for the benefit of patients and their families.…”

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

“…It was shown that an inhibitor of the eIF4F complex, which creates free eIF4E, increases the abundance of the eIF4E-CY-FIP1-FMRP complex (with a parallel decrease in the CY-FIP1-WAVE complex) in Fmr1 KO mice, and the restoration of this imbalance rescues spine and memory deficits in these animals [150]. Hence, studies of the Fmr1 KO rodent model have illuminated a variety of molecular mechanisms relevant to FXS, especially those pertinent to the regulation of protein synthesis, and may provide biological targets for therapeutic intervention [24], complementing ongoing clinical trials in human FXS patients [151,152].…”