Small molecular screening and therapeutic potential for PWS

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 including childhood obesity, hypogonadism, hyperphagia, and developmental delay. 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 hromosome 15q11-q13 region. Application of DNA methylation and histone deacetylation inhibitors (HDAC) 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. Our collaborator, Dr. Bryan Roth’s team, has recently identified a FDA approved drug from small molecule screen that specifically unsilences the Angelman syndrome Ube3a gene from paternal chromosome. Small molecule is a low molecular weight organic compound that binds with high affinity to protein, nucleic acid, or polysaccharide. We hypothesize that small molecule may be able to unsilence the PWS candidate genes including Snrpn and SnoRNAs from maternal chromosome. We propose to identify a drug-like small molecule(s) by screen small molecule library using Snrpn-EGFP as a marker. The proposed study is significant because it will lead to the development of therapeutic intervention to the PWS in humans.

Funded Year:


Awarded to:

Young-hui Jiang, MD


$50,000 (OSS Funds)


Duke University

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