Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models

Faith Conroy, Rachael Miller, Julia F. Alterman, Matthew R. Hassler, Dimas Echeverria, Bruno M. D. C. Godinho, Emily G. Knox, Ellen Sapp, Jaquelyn Sousa, Ken Yamada, Farah Mahmood, Adel Boudi, Kimberly Kegel-Gleason, Marian DiFiglia, Neil Aronin, Anastasia Khvorova () and Edith L. Pfister ()
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Faith Conroy: UMass Chan Medical School
Rachael Miller: UMass Chan Medical School
Julia F. Alterman: UMass Chan Medical School
Matthew R. Hassler: UMass Chan Medical School
Dimas Echeverria: UMass Chan Medical School
Bruno M. D. C. Godinho: UMass Chan Medical School
Emily G. Knox: UMass Chan Medical School
Ellen Sapp: Massachusetts General Hospital, Harvard Medical School
Jaquelyn Sousa: UMass Chan Medical School
Ken Yamada: UMass Chan Medical School
Farah Mahmood: Massachusetts General Hospital, Harvard Medical School
Adel Boudi: Massachusetts General Hospital, Harvard Medical School
Kimberly Kegel-Gleason: Massachusetts General Hospital, Harvard Medical School
Marian DiFiglia: Massachusetts General Hospital, Harvard Medical School
Neil Aronin: UMass Chan Medical School
Anastasia Khvorova: UMass Chan Medical School
Edith L. Pfister: UMass Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33061-x

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