The Known Unknowns: Missing Pieces in in vivo Models of Fragile X Syndrome
Pushkar Kulkarni*, Aarti Sevilimedu*
Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, 500046, India
Fragile X Syndrome (FXS) is a rare disease and the leading monogenic cause of Autism Spectrum Disorders (ASD). It is caused by the silencing of the Fragile X mental retardation (FMR1) gene and the subsequent reduction or loss of fragile X mental retardation protein (FMRP). The clinical effects seen in FXS patients are several and highly variable making it difficult to model them in a single model or even one organism. Furthermore, several human behaviours can be measured only through surrogate endpoints in animals. Therefore, it has been challenging to develop in vivo models of FXS for drug discovery.
This review endeavours to consolidate the information on all available in vivo models for FXS specifically with a focus on their suitability for drug development, with the objective of identifying gaps and potential solutions. To do so, we have summarised the major clinical characteristics and possible mechanisms underlying clinical phenotypes associated with FXS and other disorders that arise from abnormalities in the FMR1 locus, such as fragile-X associated tremor/ataxia syndrome (FXTAS), fragile-X-associated neuropsychiatric disorders (FXAND) including ASD and fragile x-associated primary ovarian insufficiency (FXPOI). We then connect clinical features to phenotypes observed in available in vivo FXS models where possible, covering a wide range of organisms from primates, rats, mice, zebrafish, fruit fly and zebra finches. For each model organism, we list the technology of model creation, phenotypes/assays, mechanistic basis of disease manifestation and specific advantages or disadvantages of the model in the context of drug discovery.
Finally, we have highlighted the missing pieces in FXS modelling and propose strategies to address them, considering aspects of modelling spectrum disorders, repeat expansion and silencing, new functions of FMRP and identification of efficacious treatments.
DOI: 10.29245/2572-9411/2020/1.1190 View / Download Pdf