{Reference Type}: Journal Article
{Title}: Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT.
{Author}: Iwamoto N;Liu Y;Frank-Kamenetsky M;Maguire A;Tseng WC;Taborn K;Kothari N;Akhtar A;Bowman K;Shelke JD;Lamattina A;Hu XS;Jang HG;Kandasamy P;Liu F;Longo K;Looby R;Meena ;Metterville J;Pan Q;Purcell-Estabrook E;Shimizu M;Prakasha PS;Standley S;Upadhyay H;Yang H;Yin Y;Zhao A;Francis C;Byrne M;Dale E;Verdine GL;Vargeese C;
{Journal}: Mol Ther Nucleic Acids
{Volume}: 35
{Issue}: 3
{Year}: 2024 Sep 10
{Factor}: 10.183
{DOI}: 10.1016/j.omtn.2024.102246
{Abstract}: 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.