한빛사논문
- 조회377
Sung Eun Wang 1,#, Yan Xiong 2,#, Mi-Ae Jang 3, Kwang-Su Park 2, Meaghan Donahue 1, Julia Velez 2, Jian Jin 2,*, Yong-hui Jiang 1,4,5,*
1Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA
2Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
3Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
4Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA
5Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA
#These authors contributed equally
*Corresponding authors: correspondence to Jian Jin or Yong-hui Jiang
Abstract
Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642 has better brain penetration, more potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable to intraperitoneal route. MS152 treatment in newborns ameliorated the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-28)
- 국내+국외 연구진
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