%0 Journal Article
%T Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT.
%A Iwamoto N
%A Liu Y
%A Frank-Kamenetsky M
%A Maguire A
%A Tseng WC
%A Taborn K
%A Kothari N
%A Akhtar A
%A Bowman K
%A Shelke JD
%A Lamattina A
%A Hu XS
%A Jang HG
%A Kandasamy P
%A Liu F
%A Longo K
%A Looby R
%A Meena 
%A Metterville J
%A Pan Q
%A Purcell-Estabrook E
%A Shimizu M
%A Prakasha PS
%A Standley S
%A Upadhyay H
%A Yang H
%A Yin Y
%A Zhao A
%A Francis C
%A Byrne M
%A Dale E
%A Verdine GL
%A Vargeese C
%J Mol Ther Nucleic Acids
%V 35
%N 3
%D 2024 Sep 10
%M 39027419
%F 10.183
%R 10.1016/j.omtn.2024.102246
%X Huntington's disease (HD) is an autosomal dominant disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in one copy of the HTT gene (mutant HTT, mHTT). The unaffected HTT gene encodes wild-type HTT (wtHTT) protein, which supports processes important for the health and function of the central nervous system. Selective lowering of mHTT for the treatment of HD may provide a benefit over nonselective HTT-lowering approaches, as it aims to preserve the beneficial activities of wtHTT. Targeting a heterozygous single-nucleotide polymorphism (SNP) where the targeted variant is on the mHTT gene is one strategy for achieving allele-selective activity. Herein, we investigated whether stereopure phosphorothioate (PS)- and phosphoryl guanidine (PN)-containing oligonucleotides can direct allele-selective mHTT lowering by targeting rs362273 (SNP3). We demonstrate that our SNP3-targeting molecules are potent, durable, and selective for mHTT in vitro and in vivo in mouse models. Through comparisons with a surrogate for the nonselective investigational compound tominersen, we also demonstrate that allele-selective molecules display equivalent potency toward mHTT with improved durability while sparing wtHTT. Our preclinical findings support the advancement of WVE-003, an investigational allele-selective compound currently in clinical testing (NCT05032196) for the treatment of patients with HD.