Heterogeneity in Fragile X Syndrome Highlights the Need for Precision Medicine-Based Treatments

Abstract

Fragile X syndrome (FXS) is the most frequent monogenic cause of autism or intellectual disability, and research on its pathogenetic mechanisms has provided important insights on this neurodevelopmental condition. Nevertheless, after 30 years of intense research, efforts to develop treatments have been mostly unsuccessful. The aim of this review is to compile evidence from existing research pointing to clinical, genetic, and therapeutic response heterogeneity in FXS and highlight the need of implementing precision medicine-based treatments. We comment on the high genetic and phenotypic heterogeneity present in FXS, as a contributing factor to the difficulties found during drug development. Given that several clinical trials have showed a non-negligeable fraction of positive responders to drugs targeting core FXS symptoms, we propose that success of clinical trials can be achieved by tackling the underlying heterogeneity in FXS by accurately stratifying patients into drug-responder subpopulations. These precision medicine-based approaches, which can be first applied to well-defined monogenic diseases such as FXS, can also serve to define drug responder profiles based on specific biomarkers or phenotypic features that can associate patients with different genetic backgrounds to a same candidate drug, thus repositioning a same drug for a larger number of patients with NDDs.

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

“…In addition, several laboratories were contacted before we found one that would test the patient's protein and mRNA level using a blood sample. In the area of clinical trials, it may eventually become necessary to stratify patients based on the severity of their condition, and this clinical research would also call for more detailed laboratory studies 47,48 …”

“…In the area of clinical trials, it may eventually become necessary to stratify patients based on the severity of their condition, and this clinical research would also call for more detailed laboratory studies. 47,48 We anticipate that Patient A will remain fully independent but numerous issues regarding genetic counseling for FXS, mental health and overall wellness still need to be addressed. His daughters would carry the gene for this condition at least in the PM state.…”

Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals

“…Aberrant mRNA translation represents one of the major hallmarks of FXS and, therefore, a putative therapeutic target [2,14,119]. While therapies aimed at rescuing protein synthesis have provided successful results in mice [120], similar approaches have failed in clinical trials, highlighting the difficulties of translating data obtained in murine models to the clinic [4,5,43,44,66,121]. Several factors may explain these failures, including the lack of patient stratification, varying ages of the enrolled FXS subjects, and the validity of the outcome measures [4,43,66].…”

“…Individuals with FXS show physical and behavioral features, including intellectual disability, attentiondeficit/hyperactivity disorder (ADHD), repetitive behaviors, and anxiety. Reduced social interactions have been reported in FXS individuals diagnosed with autism spectrum disorder (ASD) [2][3][4][5][6][7]. Indeed, around 40% of patients with FXS meet the criteria for ASD [8][9][10].…”

“…Despite the promising results obtained in Fmr1 KO mice, the use of a rodent model for FXS presents limitations that may hamper the translation of preclinical data to humans. Several clinical trials for FXS, based on findings generated in the mouse model, have not been very successful so far [4,5,43,44], suggesting that models using human patient-derived cells will be important for the development of new and personalized therapies.…”