Fragile X Syndrome Clinical Trial
Official title:
Augmentation of the Cholinergic System in Fragile X Syndrome: A Double-Blind Placebo-Controlled Randomized Study of Donepezil
Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual disability. Though recent research has revealed much about the genetic and neurobiological bases of FraX, knowledge about specific and effective treatments for affected individuals is lacking. Based on information from both human and animal studies, one cause of intellectual disability in FraX may be related to deficits in a particular brain neurotransmitter system (the "cholinergic" system). Thus, the investigators propose to use a specific medication, donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be effective, the knowledge generated by this research may also be relevant to other developmental disorders that share common disease pathways with FraX.
Fragile X syndrome (FraX), a neurodevelopmental disorder caused by mutations of the FMR1
gene, is the most common known heritable cause of cognitive and behavioral disability in
humans. Though research progress pertaining to FraX has been extraordinary in many areas,
many critical gaps in knowledge remain. In particular, there is a dearth of information on
treatments designed to address the often-serious cognitive and behavioral symptoms of FraX.
Like many other developmental disorders, descriptions of treatments for FraX that do exist
in the literature are primarily derived from uncontrolled case studies or series, with both
pharmacological and behavioral interventions targeted to symptoms associated with
phenomenologically defined "co-morbid" diagnoses such as AD/HD, autism spectrum disorders
(ASD) or anxiety disorders. These circumstances are suboptimal as such symptom-based
treatments represent a low level of specificity with respect to the underlying pathogenesis
of cognitive and behavioral problems. Accordingly, new research to develop more effective,
disease-specific treatments for persons with FraX is greatly needed.
Converging evidence from our research group and others strongly support a hypothesis of
functional cholinergic deficits contributing to cognitive-behavioral dysfunction in FraX.
This evidence includes: (1) abnormalities of cholinergic pathway function and neurochemistry
observed with functional MRI and 1H-MRS, respectively, in FraX, (2) an analysis of FMR1
expression during human fetal development indicating particularly high expression in
cholinergic brain regions, (3) cholinergic system abnormalities detected in the mouse and
fly models of FraX, (4) an analysis of the specific profile of cognitive and behavioral
deficits in FraX in relation to current knowledge of cholinergic system functions, and, (5)
significant improvements in cognition and behavior observed in 12 individuals with FraX
during an open-label trial of donepezil, a cholinesterase inhibitor. Accordingly, the
proposed project will consist of a double blind, placebo controlled trial of donepezil in 50
individuals with FraX, ages 12 to 29 years. The primary hypothesis is that subjects
receiving donepezil will show greater improvements in specific measures of behavior and
cognition, relative to the placebo group. In addition to direct benefit to persons affected
by FraX, findings from the proposed research are likely to be highly relevant to subgroups
of (currently) idiopathic developmental disorders, such as autism, that might share common
pathophysiological mechanisms of disease with FraX. Such shared mechanisms could occur
through intersecting pathways involving FMR1 protein function or as a result of similarities
in the contribution of cholinergic dysfunction to cognitive and behavioral disability.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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