Epigenomic engineering for Down syndrome

- Down syndrome (DS) is the commonest genetic cause of mental disability.
- Epigenetic modifications are implicated in neurocognitive dysfunction in DS.
- These epigenetic modifications are suitable therapeutic targets, but current therapies may have unwanted side effects.
- CRISPR-Cas9 is a precise genome editing technology that could be used to target epigenomic abnormalities in DS.
- A number of barriers − both technical and ethical − will need to be overcome for clinical translation.

Down syndrome (DS; trisomy 21), the commonest genetic cause of mental disability, affects approximately 250,000 families in the United States alone. Despite milestones in understanding the specific genetic causes of the syndrome, the major symptoms of DS − not least those related to neurocognitive function − are incurable. DS phenotypes are highly variable, and gene expression patterns cannot be explained by trisomy alone, implicating epigenetics in DS pathophysiology. DNA and histone modifications appear to contribute to DS pathology and cognitive defects, and epigenomic, and genome editing research have very recently opened up novel therapeutic avenues for several diseases including DS. Here, we discuss how epigenomic therapies might be used to ameliorate DS-related phenotypes with a particular focus on the CRISPR-Cas 9 system for targeted epigenomic engineering in DS. This approach is likely to reap rewards in terms of understanding the pathophysiology of DS, especially when combined with animal models, but significant technical and ethical challenges must be overcome for clinical translation.