Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Key Points Fragile X syndrome is a monogenic neurodevelopmental disorder associated with intellectual disability and autism spectrum disorders. Animal models have provided insights into the neurobiological mechanisms and enabled the identification of novel drug targets. Promising targets include met...
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| Published in: | Nature reviews. Drug discovery Vol. 17; no. 4; pp. 280 - 299 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01.04.2018
Nature Publishing Group |
| Subjects: | |
| ISSN: | 1474-1776, 1474-1784, 1474-1784 |
| Online Access: | Get full text |
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| Summary: | Key Points
Fragile X syndrome is a monogenic neurodevelopmental disorder associated with intellectual disability and autism spectrum disorders.
Animal models have provided insights into the neurobiological mechanisms and enabled the identification of novel drug targets.
Promising targets include metabotropic glutamate receptor 5 (mGluR5), GABA receptors and proteins that are regulated or regulate fragile X mental retardation protein 1 (FMRP).
Many compounds have been extensively investigated in preclinical studies and are able to rescue altered levels of protein synthesis, synaptic plasticity and behaviour. Behavioural phenotypes in
Fmr1
-knockout mice are difficult to measure, and the rescue of these deficits has been inconsistent across these different drugs.
Subsequent clinical trials in humans were unable to demonstrate any improvement using behavioural measures as primary end points.
Objective measures of core phenotypes such as direct assessments of cognition and language rather than secondary behaviours need to be implemented in future trials.
Very young patients have not yet been included in clinical trials, and this may be the only group in which effects of a disease-modifying agent targeting cognition and development can be seen. Efforts may need to be redirected towards the implementation of longer trials in younger children accompanied by learning interventions measuring cognitive and developmental outcomes.
In this Review, a group of experts in fragile X syndrome analyses why the considerable drug development effort based on robust preclinical findings describing the mechanisms underlying this neurodevelopmental disorder has failed to translate into effective treatment and offers possible solutions to improve clinical trial design and therapeutic approaches.
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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 |
| ISSN: | 1474-1776 1474-1784 1474-1784 |
| DOI: | 10.1038/nrd.2017.221 |