Epigenetic Silencing of HSA21 in Down Syndrome

Down Syndrome (DS) is caused by a triplication of genes on chromosome 21 (HSA21) and gives rise to mental retardation (MR). Silencing of one of three copies of HSA21 has been shown to rescue the cell phenotype. However, several technical hurdles must be overcome to allow for realistic therapeutic intervention – efficient genomic integration and specific targeting of one of the three HSA21 chrosomes. The current proposal provides new approaches which allow for efficient and specific targeting of a single HSA21 copy. Following targeting, we will assess the ability to rescue the DS phenotype in human DS iPS cells on a large scale. Normalization of gene expression and function will be assessed both by transcriptional and methylation profiling as well as examining cell function in vitro.