Yong-hui Jiang, MD, PhD
Despite the significant progress in understanding the molecular basis underlying Prader-Willi syndrome, little advance has been achieved in developing the treatment specifically targeting to the molecular defect. The SNORD116 between the SNRPN and UBE3A genes is important for the major features of PWS. The host transcripts and SNORD116 in the maternal chromosome are transcriptionally silenced by an epigenetic mechanism involving the PWS imprinting center (PWS-IC).The expression of SNORD116 cluster is processed from continuous transcripts initiated from the PWS-IC/promote region of SNRPN. One attractive strategy of developing the molecular therapy for PWS is to activate the expression of paternally expressed genes including SNORD116 from the maternal chromosome. Through a high content screening of ~10000 small molecules in mouse embryonic fibroblasts (MEF) isolated from mice carrying maternal Snrpn-EGPF fusion protein, we have identified and validated two compounds, UNC638 and UNC0642, that could activate the expression of both Snrpn and Snord116 in human cultured PWS cells. Most importantly, UNC0642 can activate the expression of Snrpn and Snord116 in the PWS mouse model with a paternal deletion from Snrpn to Ube3a (SUp-/m+). UNC-618 and UNC0642 belongs to a class of histone H3K9 methyltransferase inhibitors. Our exciting data clearly support a translational potential of this project. The ultimately goal is to launch a human trial using UNC0642 and its derivative in human PWS. The specific objective of this study is to conduct an initial preclinical study and evaluate the feasibility of epigenetic therapy in PWS. Our hypothesis is that the treatment of UNC-0642 at different ages and different routes in PWS mouse models will not only activate the expression of Snrpn and SnoRNAs from the maternal chromosome but also correct abnormal phenotypes and has minimal toxicity and off-target effect. The proposed study is certainly significant because it will lead to the development of molecular specific therapeutic intervention and first human clinical trial for PWS.
Yong-hui Jiang, MD, PhD
The Foundation for Prader-Willi Research (federal tax id 31-1763110) is a nonprofit corporation with federal tax exempt status as a public charity under section 501(c)(3).
The mission of FPWR is to eliminate the challenges of Prader-Willi syndrome through the advancement of research. High-quality research will lead to more effective treatments and an eventual cure for this disorder. By working together, we intend to free our loved ones from the burdens of PWS, allowing them to lead full and independent lives.
Foundation for Prader-Willi Research
340 S. Lemon Ave, #3620
Walnut, CA 91789