Ube3a unsilencer for the potential treatment of Angelman syndrome

被引：2

作者：

Vihma, Hanna ^{[1
]}

Li, Kelin ^{[2
]}

Welton-Arndt, Anna ^{[3
]}

Smith, Audrey L. ^{[1
]}

Bettadapur, Kiran R. ^{[1
]}

Gilmore, Rachel B. ^{[4
]}

Gao, Eric ^{[1
]}

Cotney, Justin L. ^{[4
]}

Huang, Hsueh-Cheng ^{[5
]}

Collins, Jon L. ^{[6
]}

Chamberlain, Stormy J. ^{[4
]}

Lee, Hyeong-Min ^{[1
,7
]}

Aube, Jeffrey ^{[2
,3
]}

Philpot, Benjamin D. ^{[1
]}

机构：

[1] Univ North Carolina Chapel Hill, Carolina Inst Dev Disabil, Neurosci Ctr, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA

[2] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

[3] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC 27599 USA

[4] Univ Connecticut, Sch Med, Dept Genet & Genome Sci, Farmington, CT USA

[5] Deerfield Management, Deerfield Discovery & Dev, New York, NY USA

[6] Univ North Carolina Chapel Hill, Off Vice Chancellor Res, Chapel Hill, NC USA

[7] Med Univ South Carolina, Hollings Canc Ctr, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

UBIQUITIN LIGASE; 3-AMINOPYRAZOLE INHIBITORS; ANTITUMOR AGENTS; GENE; EXPRESSION; CDK2/CYCLIN; MUTATIONS; THERAPY; CELLS;

D O I：

10.1038/s41467-024-49788-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.

引用

页数：16

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[1] Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells [J].