Exploring treatment strategies for FXS: high-throughput drug screens and the identification of potential biomarkers

Authors

• D Kumari
• M Swaroop
• A Bhattacharya
• J Nadel
• K Moulton
• NM Zeak
• A Glicksman
• C Dobkin
• DJ Brick
• N Southall
• W Huang
• PH Schwartz
• CB Smith
• E Klann
• W Zheng
• K Usdin

Abstract

Fragile X syndrome (FXS) is the most common cause of inherited cognitive disability and the most common known cause of autism. There is no cure for FXS and the available therapeutic options are limited. Identification of FMRP targets and the elucidation of molecular mechanisms involved in the disease pathology have lead to the development of drugs that target signaling pathways that are altered in the brains of FXS patients. However, these strategies are limited by the fact that loss of FMRP affects multiple pathways not all of which are fully understood. Given that the FMR1 gene is silenced in FXS by aberrant epigenetic modifications which can be reversed, and the fact that expanded CGG-repeats are not a part of the open reading frame which is otherwise normal, strategies aimed at restoring FMRP production may be worthwhile. We have developed a sensitive assay to detect FMRP that is amenable to high-throughput screening (HTS) and we have used this assay in various HTS for identifying compounds able to reactivate the silenced allele or improve translation of any existing mRNA. We have also identified a number of disease-specific markers in FXS patient cells that can be used to assess the efficacy of potential therapeutic drugs that either restore FMRP expression or target the altered signaling pathways.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Friday, March 26, 2021