Sheen, Volney L MD

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.

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. In our prior funded work, we have developed several approaches to overcome the technical hurdles to allow for therapeutic intervention – efficient genomic integration and specific targeting of one of the three HSA21 chromosomes. The current proposal seeks to address whether enhanced efficiency of silencing seen in vitro can be achieved in vivo. After lentiviral based infection of the targeting construct into the TcMAC21 DS mouse model, we will evaluate whether these mice show normalization in phenotype at the behavioral, neurophysiological, histological and genetic/epigenetic levels.

Down Syndrome (DS) is caused by a triplication of genes on chromosome 21 (HSA21) and gives rise to early onset Alzheimers disease. Recent work suggests that genes other than APP on HSA21 contribute to AD pathogenesis. The current proposal incorporates several technological methods that allow for silencing of individual and clusters of genes in one HSA21 copy, leaving the other two intact. This approach will allow for systematic testing to identify which subset of genes the AD phenotype in DS.