A publication resulting from this project was highlighted in an FPWR Research Blog post “Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome” (December 2016)
Like most genetic disorders, there is no specific therapeutic intervention targeted to the molecular defect for Prader-Willi syndrome (PWS). The clinical presentations of PWS are caused by paternal deficiency of genes in the chromosome 15q11-q13 region. Recent reports indicate a region between the SNRPN and UBE3A genes harboring SnoRNA clusters is important for the key features of PWS. The SnoRNAs in the maternal chromosome are structurally intact but transcriptionally silent. Therefore, the simple idea of treating the PWS at molecular level is to find a drug that can unsilence the SnoRNAs from maternal chromosome. The epigenetic mechanism including the DNA methylation and chromatin modification at PWS imprinting center (PWS-IC) regulates the paternal specific expression of genes including Snrpn and SnoRNAs in the chromosome 15q11-q13 region. Application of DNA methylation and histone deacetylation inhibitors can activate the expression of the SNRPN gene from the silent maternal chromosome in cells from PWS patients and PWS mouse model. These observations strongly support a possibility to unsilence the expression of the SnoRNAs from maternal chromosome by other molecular approach through the epigenetic mechanism. We hypothesize that small molecule may be able to unsilence the PWS candidate genes including Snrpn and SnoRNAs from maternal chromosome. Using embryonic fibroblasts derived from maternal Snrpn-EGFP mouse as a marker, we have performed a high content screening of 4000 small molecule compounds. We have identified a promising candidate drug that can activate the expression of Snrpn from maternal chromosome in human PWS derived fibroblasts.
These results indicated that our screening strategy is working. We then propose to 1) further characterize the drug identified in vitro and in vivo, and 2) expand the screening to 10000 small molecule compounds to identify additional candidate drugs with different specificities. The proposed study is significant because it will lead to the development of therapeutic intervention to the PWS in humans.