Chapter 6: Safety Considerations of Targeting Epigenetic Mechanisms
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Published:30 Sep 2024
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Special Collection: 2024 eBook CollectionSeries: Drug Discovery
C. A. Lovatt, S. Liu, and C. W. Scott, in Epigenetic Drug Discovery, ed. H. M. Chan and C. Arrowsmith, Royal Society of Chemistry, 2024, vol. 83, ch. 6, pp. 158-192.
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Epigenetic regulation of gene expression utilises cellular epigenetic machinery that includes enzymes that add chemical groups or ‘marks’ to DNA or histones (‘writers’), those that remove these ‘marks’ (‘erasers’) and those that recognise and bind to the ‘marks’ (‘readers’). The epigenome differs between cell, tissue and species and is dynamic and constantly changing based on factors that include development, aging, disease, nutritional status and environmental conditions, so the determination of the causality of a ‘moment in time’ epigenetic profile in the development of toxicity and disease is very challenging. Currently, the field of epigenetics research is still striving to determine what epigenetic changes are adverse, beneficial, adaptive or neutral. At the time of writing, there are no specific epigenetic-based regulatory requirements; therefore, currently, the assessment of the safety risk of epigenetic modulators is not significantly different than for other small molecules. The unique characteristics of epigenetic modulation should, however, be taken into account when designing safety studies, such as the potential for delayed toxicity and careful consideration should be made with the choice of species. The targeting of epigenetic mechanisms for novel disease therapies offers the promise of highly personalised medicines if such changes can be harnessed on an individual patient basis.