scholarly journals Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome

2020 ◽  
Vol 10 (6) ◽  
pp. 361
Author(s):  
Mittal Jasoliya ◽  
Heather Bowling ◽  
Ignacio Cortina Petrasic ◽  
Blythe Durbin-Johnson ◽  
Eric Klann ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Drug Response ◽  
Molecular Level ◽  
Fragile X ◽  
Primary Objective ◽  
Molecular Biomarkers ◽  
Target Engagement ◽  
Targeted Treatments ◽  
Expression Abundance ◽  
Metalloproteinase 9

Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.

scholarly journals The first awake simultaneous PET-MR study of an adult with fragile X syndrome: A case report

2021 ◽  
Author(s):  
Soujanya Gade ◽  
Trine Hjørnevik ◽  
Jun Hyung Park ◽  
Bin Shen ◽  
Meng Gu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Serum Cortisol ◽  
Vineland Adaptive Behavior Scales ◽  
Cortisol Reactivity ◽  
Quantitative Pet ◽  
Observation Scale ◽  
Targeted Treatments ◽  
Dorsolateral Prefrontal

Abstract Introduction: Fragile X syndrome (FXS) is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Case Presentation: a 25-year-old male with FXS participated in this study. The participant obtained scores in the non-spectrum range on the Autism Diagnostic Observation Scale and obtained an full scale IQ score of 57 (Verbal IQ = 23 and Nonverbal IQ = 34) on the Stanford-Binet Intelligence Scales (SB-5). On the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-2) he obtained a composite score of 66. Pre-scan serum cortisol reactivity was 16.45 mcg/dL. Following a [18F]flumazenil (5mCi) intravenous bolus injection, the participant was scanned without sedation on a hybrid PET-MR system (Signa, GE Healthcare, Waukesha, WI) for 60 mins. List mode PET data, structural and diffusion MRI (DWI), and MR spectroscopy (MRS) were acquired simultaneously. Quantitative PET and DWI measures were extracted from 83 pre-defined regions of interest. MRS data was collected from two 20 cc voxels (thalamus and dorsolateral prefrontal cortex). Conclusion: This is the first study to investigate neuromolecular behavior in FXS without the use of sedation using PET-MR. Mapping the neuromolecular differences in FXS can lead to targeted treatments that can significantly improve quality of life for families and individuals with intellectual disabilities.

Targeted treatments in fragile X syndrome

2014 ◽  
Vol 2 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Emma B Hare ◽  
Randi J Hagerman ◽  
Reymundo Lozano
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Targeted Treatments

scholarly journals Baclofen-Associated Neurophysiologic Target Engagement Across Species in Fragile X Syndrome

2021 ◽  
Author(s):  
Carrie R. Jonak ◽  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Samantha A. Assad ◽  
Manbir S. Sandhu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Gamma Activity ◽  
Multielectrode Array ◽  
Target Engagement ◽  
Human Experiments ◽  
Gamma Power ◽  
Delayed Language Development

Abstract Background: Fragile X Syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. Methods: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). Results: In Fmr1 KO mice and in humans with FXS, baclofen use was synchronously associated with suppression of elevated gamma power and increase in theta power at rest. In the Frm1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. Conclusions: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. Trial Registration: The human experiments are registered under NCT02998151.

scholarly journals Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

2014 ◽  
Vol 34 (30) ◽  
pp. 9867-9879 ◽  
Author(s):  
H. Sidhu ◽  
L. E. Dansie ◽  
P. W. Hickmott ◽  
D. W. Ethell ◽  
I. M. Ethell
Keyword(s):  
Mouse Model ◽  
Matrix Metalloproteinase ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Matrix Metalloproteinase 9 ◽  
Metalloproteinase 9

scholarly journals Fragile X Syndrome and Targeted Treatments

2020 ◽  
Vol 6 (1) ◽  
pp. 23-33 ◽  
Author(s):  
Nattaporn Tassanakijpanich ◽  
Ana María Cabal-Herrera ◽  
Maria Jimena Salcedo-Arellano ◽  
Randi Jenssen Hagerman
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Animal Studies ◽  
Fragile X ◽  
Clinical Use ◽  
Pharmacological Treatments ◽  
Knock Out ◽  
Fragile X Mental Retardation ◽  
Targeted Treatments ◽  
The Many

Many targeted treatment studies have been carried out in individuals with Fragile X Syndrome (FXS) guided by animal studies from the Fragile X Mental Retardation 1 (FMR1) knock out (KO) mice and the fragile X Drosophila studies. Here we review the many medications that have been studied in patients with FXS and some of these medications are available for clinical use by wise clinicians. Other medications are not currently available by prescription because they are not approved by the FDA. No medication has received specific approval for treatment of FXS, although some have shown benefit from clinical studies. There is much to be done in the treatment of those with FXS and this report describes those pharmacological treatments that target the neurobiological mechanisms that are dysregulated by the lack of the Fragile X Protein (FMRP) in those with FXS.

scholarly journals Review of targeted treatments in fragile X syndrome

2016 ◽  
Vol 5 (3) ◽  
pp. 158-167 ◽  
Author(s):  
Andrew Ligsay ◽  
Randi J Hagerman
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Targeted Treatments

scholarly journals Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Florence Morin-Parent ◽  
Camille Champigny ◽  
Angelina Lacroix ◽  
François Corbin ◽  
Jean-François Lepage
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Short Interval ◽  
Silent Period ◽  
Intracortical Inhibition ◽  
Primary Objective ◽  
Healthy Controls ◽  
Intracortical Facilitation ◽  
Cortical Hyperexcitability ◽  
Resting Motor Threshold

AbstractFragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.

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