Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective

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.

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Molecular Biomarkers in Fragile X Syndrome

Brain Sciences ◽

10.3390/brainsci9050096 ◽

2019 ◽

Vol 9 (5) ◽

pp. 96 ◽

Cited By ~ 5

Author(s):

Zafarullah ◽

Tassone

Keyword(s):

Clinical Trials ◽

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Autism Spectrum ◽

Molecular Biomarkers ◽

Synaptic Function ◽

Primary Role ◽

Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

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New Targeted Treatments for Fragile X Syndrome

Current Pediatric Reviews ◽

10.2174/1573396315666190625110748 ◽

2019 ◽

Vol 15 (4) ◽

pp. 251-258 ◽

Cited By ~ 1

Author(s):

Dragana Protic ◽

Maria J. Salcedo-Arellano ◽

Jeanne Barbara Dy ◽

Laura A. Potter ◽

Randi J. Hagerman

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Behavioral Problems ◽

Rna Binding ◽

Fragile X ◽

Symptomatic Treatment ◽

Fmr1 Gene ◽

Fragile X Mental Retardation ◽

Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

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An “Omic” Overview of Fragile X Syndrome

Biology ◽

10.3390/biology10050433 ◽

2021 ◽

Vol 10 (5) ◽

pp. 433

Author(s):

Olivier Dionne ◽

François Corbin

Keyword(s):

Mental Retardation ◽

Fragile X Syndrome ◽

Molecular Mechanisms ◽

Rna Binding ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Medical Problems ◽

Biochemical Alterations ◽

Fragile X Mental Retardation ◽

Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

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Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.730987 ◽

2021 ◽

Vol 12 ◽

Author(s):

Truong An Bui ◽

Julie Shatto ◽

Tania Cuppens ◽

Arnaud Droit ◽

François V. Bolduc

Keyword(s):

Clinical Trials ◽

Fragile X Syndrome ◽

Fragile X ◽

Single Gene ◽

Specific Treatment ◽

Autism Spectrum ◽

New Paradigm ◽

Trade Offs ◽

Wide Range ◽

The Impact

Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.

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Fragile X mental retardation protein is a size-dependent translational activator

10.1101/257204 ◽

2018 ◽

Author(s):

Ethan J. Greenblatt ◽

Allan C. Spradling

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X ◽

Ovarian Follicle ◽

Autism Spectrum ◽

Ribosome Profiling ◽

Large Proteins ◽

Fragile X Mental Retardation ◽

Stored Mrna ◽

Neural Dysfunction

SummaryFMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conserved Fragile X mental retardation gene (Fmr1) cause the most common inherited human intellectual disability/autism spectrum disorder. Fmr1 is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescent Drosophila oocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.

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Fragile X Syndrome

Colombia Medica ◽

10.25100/cm.v45i4.1810 ◽

2014 ◽

pp. 190-198 ◽

Cited By ~ 45

Author(s):

Wilmar Saldarriaga ◽

Flora Tassone ◽

Laura Yuriko González-Teshima ◽

Jose Vicente Forero-Forero ◽

Sebastián Ayala-Zapata ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Gene Promoter ◽

Molecular Techniques ◽

Pharmaceutical Management ◽

Developmental Problems ◽

Fragile X Mental Retardation ◽

Cgg Repeats

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

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An ‘’Omic’’ Overview of Fragile X Syndrome

10.20944/preprints202103.0643.v1 ◽

2021 ◽

Author(s):

Olivier Dionne ◽

François Corbin

Keyword(s):

Mental Retardation ◽

Fragile X Syndrome ◽

Molecular Mechanisms ◽

Rna Binding ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Therapeutic Approaches ◽

Medical Problems ◽

Fragile X Mental Retardation ◽

Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene, and consequently, in the absence of its encoded protein, FMRP (Fragile X Mental Retardation Protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focus on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into human, as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspectives the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. In this review, FMRP’s involvement on noteworthy molecular mechanisms are pointed out; ultimately contributing to various biochemicals alterations composing the fragile X phenotype.

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Experiences of the Molecular Diagnosis of Fragile X Syndrome in Ecuador

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.716311 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juan Pozo-Palacios ◽

Arianne Llamos-Paneque ◽

Christian Rivas ◽

Emily Onofre ◽

Andrea López-Cáceres ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Molecular Diagnosis ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Geographical Area ◽

Cgg Repeat ◽

Common Cause ◽

Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12–43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

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FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽

10.3390/diagnostics11101780 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1780

Author(s):

Mark Roth ◽

Lucienne Ronco ◽

Diego Cadavid ◽

Blythe Durbin-Johnson ◽

Randi J. Hagerman ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Peripheral Blood ◽

Fragile X ◽

Repeat Expansion ◽

Repeat Number ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

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Towards Mechanism-Based Treatments for Fragile X Syndrome

Brain Sciences ◽

10.3390/brainsci9080202 ◽

2019 ◽

Vol 9 (8) ◽

pp. 202

Author(s):

Daman Kumari ◽

Inbal Gazy

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Autism Spectrum ◽

Spectrum Disorder

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...]

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