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Journal of Neurodevelopmental Disorders

, 9:7

Refining translational treatment development in fragile X syndrome: Lessons learned and future directions


Our understanding of fragile X syndrome FXS pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

KeywordsFragile X syndrome Translational treatment Targeted treatments Drug development Genetic disorder AbbreviationsABCAberrant Behavior Checklist-Community

ABC-IABC Irritability

ABC-SAABC Social Avoidance

ABC-SWAberrant Behavior Checklist Social Withdrawal subscale

ADHDAttention deficit hyperactivity disorder

ADHD-RSAttention deficit hyperactivity disorder rating scale

ADHD-RS-IVADHD Rating Scale 4th Edition

ALSAmyotrophic lateral sclerosis

AMPARα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor

APPAmyloid precursor protein

ASDAutism spectrum disorder

BDNFBrain-derived neurotrophic factor

CARSChildhood autism rating scale

CGGCytosine guanine guanine

CNTContingency Naming Test

ERK; ERK1-2Extracellular signal-related kinase

ERPsEvent-related potentials

FDAFood and Drug Administration

FMR1Fragile X mental retardation gene

FMRPFragile X mental retardation protein

FXSFragile X syndrome

GABAγ-Aminobutyric acid

GSK-3bGlycogen synthase kinase-3 beta

HIVHuman immunodeficiency virus

IGF-1Insulin-like growth factor 1

iPSCInduced pluripotent stem cell


KiTAPTest of attentional performance for children


LTDLong-term depression

LTPLong-term potentiation

MDXMetadoxine ER

mGluRsGroup I metabotropic glutamate receptors

MMP-9Matrix metalloproteinase 9

MSELMullen Scales of Early Learning

mTORMammalian target of rapamycin


PETPositron emission tomography

PPIPrepulse inhibition

RBANSRepeatable Battery for the Assessment of Neuropsychological Status

SRSSocial responsiveness scale

SSRIsSelective serotonin reuptake inhibitors

TBITraumatic brain injury

UTRUntranslated region

VASVisual analog scale

Vineland-IIVineland adaptive behavior scale

Autor: Craig A. Erickson - Matthew H. Davenport - Tori L. Schaefer - Logan K. Wink - Ernest V. Pedapati - John A. Sweeney - S


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