Conroy, FaithMiller, RachaelAlterman, Julia FHassler, Matthew REcheverria, DimasGodinho, Bruno M D CKnox, Emily GSapp, EllenSousa, JacquelynYamada, KenMahmood, FarahBoudi, AdelKegel-Gleason, KimberlyDiFiglia, MarianAronin, NeilKhvorova, AnastasiaPfister, Edith L2023-01-302023-01-302022-10-03Conroy F, Miller R, Alterman JF, Hassler MR, Echeverria D, Godinho BMDC, Knox EG, Sapp E, Sousa J, Yamada K, Mahmood F, Boudi A, Kegel-Gleason K, DiFiglia M, Aronin N, Khvorova A, Pfister EL. Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models. Nat Commun. 2022 Oct 3;13(1):5802. doi: 10.1038/s41467-022-33061-x. PMID: 36192390; PMCID: PMC9530163.2041-172310.1038/s41467-022-33061-x36192390https://hdl.handle.net/20.500.14038/51611Small interfering RNAs are a new class of drugs, exhibiting sequence-driven, potent, and sustained silencing of gene expression in vivo. We recently demonstrated that siRNA chemical architectures can be optimized to provide efficient delivery to the CNS, enabling development of CNS-targeted therapeutics. Many genetically-defined neurodegenerative disorders are dominant, favoring selective silencing of the mutant allele. In some cases, successfully targeting the mutant allele requires targeting single nucleotide polymorphism (SNP) heterozygosities. Here, we use Huntington's disease (HD) as a model. The optimized compound exhibits selective silencing of mutant huntingtin protein in patient-derived cells and throughout the HD mouse brain, demonstrating SNP-based allele-specific RNAi silencing of gene expression in vivo in the CNS. Targeting a disease-causing allele using RNAi-based therapies could be helpful in a range of dominant CNS disorders where maintaining wild-type expression is essential.enOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2022; Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Journal ArticleNature communications