Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Abstract

Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder

“…Both allopregnanolone and ganaxolone hold promise to treat FXSDs, and studies with gaboxidol are planned. It is important to remark that other agents that indirectly influence the GABA deficits in FXS include the IGF-1 analogue, which is currently undergoing multicenter trials in FXS [133, 134], and cannabinoids [135], for which trials will begin soon in FXS. It is likely that GABAergic agents will continue to be part of a multimodality treatment for FXSDs for many years to come.…”

Fragile X syndrome: A review of clinical management

“…The diagnosis and treatment of the medical problems in FXS are described here and the treatment of behavioral problems are described elsewhere including the use of targeted treatments to reverse the cognitive and behavioral problems (147,148). Many of the medical problems in FXS, such as OM, MVP, GERD, hernias, joint dislocation, and flat feet are related to the connective tissue problems inherent in the syndrome.…”

Review of targeted treatments in fragile X syndrome

“…The mGluR theory of FXS states that lack of FMRP allows mGluR-mediated LTD to become hyperactive, and thus lead to features associated with FXS. This theory has been validated through observed defects at the cellular level and correlating these with behavioral abnormalities across multiple animal models (4). Moreover, studies in Fmr1 KO mice with partial reduction of mGluR expression showed correction of many of these abnormalities further demonstrating mGluRs play a significant role in the pathophysiology of FXS (20).…”

“…Above this threshold, the gene becomes methylated and silenced, resulting in significantly reduced or absent levels of the FMR1 gene product (FMRP). FMRP is a RNA-binding protein that is heavily expressed in neurons (2,3), and functions in the stability, localization, and translation of select mRNAs (4).…”