Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy

AbstractFragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer’s disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

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Effects of the Sigma-1 Receptor Agonist Blarcamesine in a Murine Model of Fragile X Syndrome: Neurobehavioral Phenotypes and Receptor Occupancy

10.21203/rs.3.rs-189177/v1 ◽

2021 ◽

Author(s):

Samantha T. Reyes ◽

Robert M.J. Deacon ◽

Scarlett G. Guo ◽

Jessa B. Castillo ◽

Berend van der Wildt ◽

...

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Regional Distribution ◽

Receptor Occupancy ◽

Autism Spectrum ◽

Contextual Fear Conditioning ◽

Synaptic Function ◽

Sigma 1 Receptor ◽

Sigma 1

Abstract Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS’ cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R’s role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for two weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored pAkt and BDNF levels, two major signaling markers, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug’s dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrate that the same doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

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Fragile X syndrome, the search for a targeted treatment

Journal of Biomedicine and Translational Research ◽

10.14710/jbtr.v5i1.3925 ◽

2019 ◽

Vol 5 (1) ◽

pp. 12

Author(s):

Shimriet Zeidler ◽

Rob Willemsen

Keyword(s):

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Short Review ◽

Autism Spectrum ◽

Targeted Treatment ◽

Adequate Treatment ◽

Model Studies ◽

Physical Problems ◽

Spectrum Disorders

Fragile X syndrome (FXS), the most common monogenetic cause of intellectual disability and autism spectrum disorders, is characterized by behavioral and physical problems. There is currently no adequate treatment available. While animal model studies seemed extremely promising, no success has been achieved in the larger clinical trials with human FXS patients. This short review describes the steps that have been taken in the development of a targeted treatment for FXS. Possible reasons for the lack of translation between animal models and human FXS patients are being explored and solutions are being proposed. The FXS story illustrates pitfalls and possibilities in translational research, that might especially be applicable for other neurodevelopmental disorders as well.

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Attention Bias and Prodromal Anxiety Symptoms in Toddlers With Fragile X Syndrome and Down Syndrome

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944-7558-126.2.167 ◽

2021 ◽

Vol 126 (2) ◽

pp. 167-181

Author(s):

Kayla Smith ◽

Abigail L. Hogan ◽

Elizabeth Will ◽

Jane E. Roberts

Keyword(s):

Down Syndrome ◽

Fragile X Syndrome ◽

Symptom Severity ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Autism Spectrum ◽

Behavioral Risk ◽

Typically Developing ◽

Attentional Avoidance ◽

Underlying Mechanisms

Abstract Early identification of behavioral risk markers for anxiety is essential to optimize long-term outcomes in children with neurodevelopmental disorders. This study analyzed attentional avoidance and its relation to anxiety and autism spectrum disorder (ASD) symptomatology during social and nonsocial fear conditions in toddlers with fragile X syndrome (FXS) and Down syndrome (DS). Toddlers with FXS and DS exhibited increased nonsocial attentional avoidance relative to typically developing (TD) toddlers. Attentional avoidance was not related to anxiety symptom severity in any group; however, higher ASD symptom severity was related to more social attentional avoidance in the FXS and TD groups. Findings suggest that there may be different underlying mechanisms driving attentional avoidance across neurodevelopmental disorders.

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A Longitudinal Study of Parent-Child Interactions and Language Outcomes in Fragile X Syndrome and Other Neurodevelopmental Disorders

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.718572 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lauren Bush ◽

Gary E. Martin ◽

Emily Landau ◽

Molly Losh

Keyword(s):

Fragile X Syndrome ◽

Language Impairment ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Autism Spectrum ◽

Pragmatic Language ◽

Language Outcomes ◽

Targeted Interventions ◽

Parent Child Interactions ◽

Parent Child

Difficulties with pragmatic language (i.e., language in social contexts, such as conversational ability) are a noted characteristic of the language profiles of both fragile X syndrome (FXS) and autism spectrum disorder (ASD), conditions which show significant phenotypic overlap. Understanding the origins and developmental course of pragmatic language problems in FXS and other developmental conditions associated with language impairment is a critical step for the development of targeted interventions to promote communicative competence across the lifespan. This study examined pragmatic language in the context of parent-child interactions in school-age children with FXS (who did and did not meet ASD criteria on the ADOS; n = 85), idiopathic ASD (n = 32), Down syndrome (DS; n = 38), and typical development (TD; n = 39), and their parents. Parent-child communicative interactions were examined across multiple contexts, across groups, and in relationship to pragmatic language outcomes assessed 2 years later. Results showed both overlapping and divergent patterns across the FXS-ASD and idiopathic ASD child and parent groups, and also highlighted key differences in pragmatic profiles based on situational context, with more pragmatic language difficulties occurring for both ASD groups in less structured interactions. Differences in parental language styles during parent-child interactions were associated with child language outcomes, likely reflecting the complex interplay of discourse style inherent to a parent, with the inevitable influence of child characteristics on parent language as well. Together, findings help delineate the dynamic and multifactorial nature of impaired pragmatic skills among children with FXS and other neurodevelopmental disorders associated with language impairment, with potential implications for the development of targeted interventions for pragmatic communication skills.

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The mouse model of fragile X syndrome exhibits deficits in contagious itch behavior

Scientific Reports ◽

10.1038/s41598-020-72891-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rodrigo Gonzales-Rojas ◽

Amtul-Noor Rana ◽

Peter Mason ◽

Christopher Renfro ◽

Vallabhi Annaluru ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Assessment Tool ◽

Fragile X ◽

Autism Spectrum ◽

Assessment Tools ◽

Learning Ability ◽

Typically Developing ◽

Spectrum Disorders

Abstract Individuals with autism spectrum disorders (ASDs) imitate observed behavior less than age-matched and typically developing peers, resulting in deterred learning ability and social interaction. However, this deficit lacks preclinical assessment tools. A previous study has shown that mice exhibit contagious itch behavior while viewing a scratching demonstrator mouse, as opposed to an ambulating demonstrator mouse, but whether autism mouse models imitate observed scratching behavior remains unknown. Here, we investigated contagious itch behavior in the mouse model of fragile X syndrome (FXS), a common form of inherited intellectual disabilities with a high risk for ASDs. We found that the mouse model of FXS shows deficits in contagious itch behavior. Our findings can be used as a new preclinical assessment tool for measuring imitative deficits in the study of neurodevelopmental disorders including FXS.

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A Comparative Study of Sociability in Angelman, Cornelia de Lange, Fragile X, Down and Rubinstein Taybi Syndromes and Autism Spectrum Disorder

American Journal on Intellectual and Developmental Disabilities ◽

10.1352/1944-7558-121.6.465 ◽

2016 ◽

Vol 121 (6) ◽

pp. 465-486 ◽

Cited By ~ 14

Author(s):

Joanna Moss ◽

Lisa Nelson ◽

Laurie Powis ◽

Jane Waite ◽

Caroline Richards ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Down Syndrome ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Neurodevelopmental Disorders ◽

Fragile X ◽

Selective Mutism ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Cornelia De Lange

Abstract Few comparative studies have evaluated the heterogeneity of sociability across a range of neurodevelopmental disorders. The Sociability Questionnaire for People with Intellectual Disability (SQID) was completed by caregivers of individuals with Cornelia de Lange (n = 98), Angelman (n = 66), Fragile X (n = 142), Down (n = 117) and Rubinstein Taybi (n = 88) syndromes and autism spectrum disorder (ASD; n = 107). Between groups and age-band (<12yrs; 12–18yrs; >18yrs) comparisons of SQID scores were conducted. Rates of behaviors indicative of selective mutism were also examined. Fragile X syndrome achieved the lowest SQID scores. Cornelia de Lange, ASD, and Fragile X groups scored significantly lower than Angelman, Down and Rubinstein Taybi groups. Selective mutism characteristics were highest in Cornelia de Lange (40%) followed by Fragile X (17.8%) and ASD (18.2%). Age-band differences were identified in Cornelia de Lange and Down syndrome.

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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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