Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome.

Autor:	Wang SE; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA., Xiong Y; Mount 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, USA., Jang MA; Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea., Park KS; Mount 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, USA., Donahue M; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA., Velez J; Mount 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, USA., Jin J; Mount 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, USA. Electronic address: jian.jin@mssm.edu., Jiang YH; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA; Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520, USA. Electronic address: yong-hui.jiang@yale.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Aug 07; Vol. 32 (8), pp. 2662-2675. Date of Electronic Publication: 2024 May 24.
DOI:	10.1016/j.ymthe.2024.05.034
Abstrakt:	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 and greater 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 with the intraperitoneal route. MS152 treatment in newborns ameliorates 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. Competing Interests: Declaration of interests J.J. is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc., Accent Therapeutics, Inc, and Tavotek Biotherapeutics, Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc., and Cullinan Oncology, Inc. Y.-H.J. is a co-founder of, has an equity interest in, is a scientific advisor to, and has an unpaid seat on the board of directors to Couragene, Inc., a biotechnology company that has licensed my intellectual property. However, Couragene did not have any direct role in this paper. J.J., Y.X., Y.-H.J., and S.W. are described in a patent application for MS1262 and MS152 as inventors, titled “G9A/GLP INHIBITORS AND METHODS OF USE” and “G9a/EHMT2 inhibitor use for Prader-Willi syndrome,” which were filed in the U.S. Patent and Trademark Office as application 63/515,010 (the “Application”). (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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