Abstract
Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.
Highlights
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the second most common cause of intellectual disability after Down syndrome [1,2]
FXS is a genetic disorder caused by the expansion of over 200 cytosine–guanine–guanine (CGG) triplet repeats in the fragile X mental retardation 1 (FMR1) gene on the X chromosome [4]
Research into these abnormalities and related/downstream effects has resulted in the identification of a large number of potential therapeutic targets, with the most data having been collected on effects of mGluR5 antagonists (2-methyl-6-(phenylethynyl)pyridine (MPEP), fenobam, 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), AFQ056, STX107, RO4917526), and GABA receptor activators [10,18]
Summary
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the second most common cause of intellectual disability after Down syndrome [1,2]. Males with premutation may develop fragile X-associated tremor/ataxia syndrome (FXTAS), an adult onset neurodegenerative disorder. FMR1 genes with CGG repeat lengths of 45–54 are classified as intermediate or grey zone alleles. It is not yet clear whether these small expansions are related to an increased risk of disease [4]. Some individuals express the full mutation in some cells and premutation in others [6] This “size mosaicism” can result in a milder and even mixed clinical picture, with the presence of both FXS and FXTAS having been described in a very small number of cases of older individuals with FXS. These estimates translate to approximately 430,000 male and close to 1 million female premutation carriers in the US
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