Editors' ChoiceGene Therapy

XIST-ing Down Syndrome

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Science Translational Medicine  21 Aug 2013:
Vol. 5, Issue 199, pp. 199ec138
DOI: 10.1126/scitranslmed.3007253

Genetic lesions can be ranked by the gravity of the disease—but also by the magnitude of the lesion. With new modern genetic techniques such as TALEN and CRISPR, one can envision a future in which the repair of a point mutation or deletion with gene therapy is routine. More problematic is the correction of abnormal chromosome numbers, in which the defect can result in newly acquired or hereditary pathologies. A recent paper from Jiang et al. reports a fundamentally new approach for repairing large chromosomal abnormalities. In this study, the researchers inactivate an entire chromosome 21—which, when triplicated, causes a common intellectual disability, namely, Down syndrome.

In an elegant set of experiments, Jiang et al. developed an in vitro system that allowed the inducible silencing of the extra chromosome 21 in human cells derived from Down syndrome patients. The authors borrowed a natural mechanism that is used by cells to compensate for the extra copies of X-linked genes in mammalian females (XX) as compared with males (XY). To avoid excess X-linked gene expression, female cells randomly inactivate one of the two X chromosomes. So-called X inactivation originates from a large noncoding RNA called XIST that is expressed exclusively from the inactive X chromosome and leads to its epigenetic silencing. Using zinc finger–based genome editing in pluripotent stem cells from Down’s syndrome patients, the authors artificially planted the XIST transgene in one of the three chromosomes 21. As in X chromosome inactivation, the expression of XIST RNA triggered stable heterochromatin modifications, DNA methylation, and chromosome-wide transcriptional silencing of the targeted chromosome 21.

Genomic expression changes and cellular pathologies of individual trisomy 21 patients can now be studied in single induced pluripotent stem cell clones in the presence and absence of the extra chromosome 21. Several important questions remain to be addressed: What is the efficiency of silencing in female cells? Would this method interfere with endogenous X-inactivation? Nevertheless, this exciting tool points the gene therapy field toward promising future approaches.

J. Jiang et al., Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013). [Abstract]

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