Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Name
2017FXSlessonslearned.pdf
Description
Accepted version
Size
703.72 KB
Format
Adobe PDF
Checksum (MD5)
b0272dea2178783af02c21109db011b5
Author(s)
Berry-Kravis, Elizabeth M.
Lindemann, Lothar
Jønch, Aia E.
Apostol, George
Bear, Mark
Carpenter, Randall L
Crawley, Jacqueline N.
Curie, Aurore
Des Portes, Vincent
Hossain, Farah
Date Issued
December 2017
Journal
Nature Reviews Drug Discovery
Publisher
Springer Science and Business Media LLC
Citation
Berry-Kravis, E. M. "Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome." Nature Reviews Drug Discovery 17, 4 (December 2017): 280–299 © 2018 Macmillan Publishers Limited, part of Springer Nature
Version
Author's final manuscript
Abstract
Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABA B receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.
MIT Department
Picower Institute for Learning and Memory
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/nrd.2017.221
