Abstract

Small 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.

Chemically modified siRNAs distinguish between mutant and normal huntingtin based on a single nucleotide difference and lower mutant huntingtin specifically in patient derived cells and in a mouse model of Huntington’s disease.

Details

Title
Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models
Author
Conroy, Faith 1 ; Miller, Rachael 1   VIAFID ORCID Logo  ; Alterman, Julia F. 2 ; Hassler, Matthew R. 2 ; Echeverria, Dimas 2 ; Godinho, Bruno M. D. C. 2   VIAFID ORCID Logo  ; Knox, Emily G. 2 ; Sapp, Ellen 3 ; Sousa, Jaquelyn 4 ; Yamada, Ken 4 ; Mahmood, Farah 3 ; Boudi, Adel 3 ; Kegel-Gleason, Kimberly 3 ; DiFiglia, Marian 3 ; Aronin, Neil 5 ; Khvorova, Anastasia 4   VIAFID ORCID Logo  ; Pfister, Edith L. 6   VIAFID ORCID Logo 

 UMass Chan Medical School, Department of Medicine, Worcester, USA 
 UMass Chan Medical School, RNA Therapeutics Institute, Worcester, USA 
 Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
 UMass Chan Medical School, RNA Therapeutics Institute, Worcester, USA (GRID:grid.38142.3c) 
 UMass Chan Medical School, Department of Medicine, Worcester, USA (GRID:grid.38142.3c); UMass Chan Medical School, RNA Therapeutics Institute, Worcester, USA (GRID:grid.38142.3c) 
 UMass Chan Medical School, Department of Medicine, Worcester, USA (GRID:grid.38142.3c) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2720702191
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.