Best Practices in Fragile X Syndrome Treatment Development

Abstract

Preclinical studies using animal models of fragile X syndrome have yielded several agents that rescue a wide variety of phenotypes. However, translation of these treatments to humans with the disorder has not yet been successful, shedding light on a variety of limitations with both animal models and human trial design. As members of the Clinical Trials Committee of the National Fragile X Foundation, we have discussed a variety of recommendations at the level of preclinical development, transition from preclinical to human projects, family involvement, and multi-site trial planning. Our recommendations are made with the vision that effective new treatment will lie at the intersection of innovation, rigorous and reproducible research, and stakeholder involvement.

Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity

“…There have been several publications, some emerging from recent NIH-convened working groups, that have outlined the requirements for adequate outcome measures for treatment studies in the ID field [7,16,17,19,25]. In general, there has been a push for outcome measures that are directly administered to the participant rather than relying on informant report, especially when the informant is a parent or care provider, because of the susceptibility of such measures to placebo effects [29], although there are ongoing attempts to create informant-report measures that are resistant to such effects.…”

“…This heterogeneity makes it difficult to find a single measure that can be appropriate for characterizing all, or even most, individuals with FXS. Unfortunately, the designation of a single outcome measure as primary is required for deciding on the efficacy of the drug in these trials [29]. Thus, there is a pressing need for psychometrically adequate outcome measures that have a wide range of applicability in terms of participant characteristics.…”

The Urgent Need for Molecular Imaging to Confirm Target Engagement for Clinical Trials of Fragile X Syndrome and Other Subtypes of Autism Spectrum Disorder

“…Although the FMR1 mouse model has propelled much interest in the FXS field, number of failed clinical trials unfolded in an attempt to establish the efficacy of these compounds. Rigorous preclinical trials must be conducted to establish the efficacy of potentially beneficial agents before accomplishing human clinical trials (2). The vast majority of twenty-two controlled clinical trials in FXS, the most among all neurodevelopmental disorders, targeted the core inhibitory/excitatory imbalance characteristic of FXS (1).…”

“…Fragile X syndrome (FXS) leads the way for targeted treatments in autism spectrum disorder (ASD) as its most common known single gene cause (1)(2)(3). FXS is typically caused by an expansion (> 200, full mutation) of a CGG repeat in the promoter region of the fragile X mental retardation 1 (FMR1) gene, leading to complete or partial methylation of the promoter and insufficient fragile X mental retardation protein (FMRP) (4).…”

Evaluating Social Interactions Using the Autism Screening Instrument for Education Planning-3rd Edition (ASIEP-3): Interaction Assessment in Children and Adults with Fragile X Syndrome

“…Other problems have included a poor availability of outcome measures and biomarkers across the FXS phenotype and a lack of well-validated cognitive measures, especially in the large subset of individuals with FXS with very limited language skills and low cognitive abilities. These challenges have contributed to an over-reliance on subjective outcome measures that are based solely on parental reports [37][38][39].…”