Special Issue "Update on the Treatment of Fragile X Syndrome"
Deadline for manuscript submissions: closed (15 June 2020).
Interests: fragile X syndrome; clinical trials; targeted treatments; autism; autism spectrum disorder; fragile X premutation; fragile X-associated disorders
2. MIND Institute, Department of Neurology, School of Medicine, University of California, Davis, CA 95817, USA
Interests: genetic intellectual disability and autism spectrum disorder; outcome measures; biomarkers; animal models of neurodevelopmental disorders
2. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA
Interests: translational medicine; neurodevelopmental disorders; fragile X syndrome; autism spectrum disorder; Angelman Syndrome; clinical trials
Fragile X syndrome (FXS) is a well-defined genetic cause of inherited intellectual disability (ID). It is also the best-understood single-gene factor associated with autism spectrum disorder (ASD), which is purely behaviorally defined. Approximately 1%–3% of the general population is affected by IDs that are often comorbid with idiopathic ASD. Deficits in the fragile X gene’s key protein seem to be the critical unifying factor linked, at a synaptic level, to dysfunction in brain pathways and to at least some aspects of behavioral symptoms in idiopathic ASD. Indeed, FXS and idiopathic ASD may present with substantial overlap in molecular pathology and clinical and behavioral features, including ID, social interaction anxiety, and inattention. Thus, further advances in the understanding of FXS may help to inform studies on ID and other ASD in highly heterogenous idiopathic ASD. Currently, there is no FDA-approved treatment for FXS. Pharmacological interventions use a symptom-based approach to manage associated (as opposed to the core) symptoms in both FXS and ASD. However, in last decade, major progress in elucidating the underlying causes of FXS has generated new targeted approaches to manage them. Indeed, among all neurodevelopmental disabilities, FXS has been at the forefront of efforts to test preclinical evidence for these interventions in clinical studies. Yet, translating these findings into clinical trials with humans with FXS has proven to be a major challenge due to a lack of objective and/or directly observable quantitative measures of brain function. Other challenges include heterogeneity in the clinical presentation of FXS and environmental factors (placebo effect). In an ongoing effort to tackle the challenges, our group recently detailed best practices in FXS treatment development. Among them was a compelling need to include the use of extensive objective and/or directly observable quantitative measures of brain function, communication, and behavior in order to determine clinically-relevant sensitive changes with treatment. Additionally, a process of de-risking large-scale multi-site projects in FXS should be carried out, for example, utilizing well-conceived proof of concept early human studies of drugs for which there is improvement of a directly translatable animal marker (e.g., event-related potential (ERP) abnormality).
In this issue, we focus on the objective and/or directly observable quantitative measures of FXS pathophysiology of meaningful relevance not only to the treatment challenges but also to understanding the developmental trajectory in FXS, including novel topics with implications on ASD and ID. Examples of the aforementioned measures include language sampling, EEG/ERP, eye tracking, Transcranial magnetic stimulation (TMS), and blood assays. Examples of topics beyond placebo effects in FXS clincial trials to include are adaptive designs and cognitive endpoints (NIH Toolbox updates). In addition, possibilities of applying remote clinical trials using web tools and statistical analyses including selection of key secondary endpoints for pivotal trials are presented.
Dr. Dejan B. Budimirovic
Dr. Walter E. Kaufmann
Dr. Craig A. Erickson
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- fragile X syndrome
- intellectual diability
- autism spectrum disorder
- clinical trials
- placebo effect
- quantitative measures