Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT .

Autor:	Iwamoto N; Wave Life Sciences, Cambridge, MA 02138, USA., Liu Y; Wave Life Sciences, Cambridge, MA 02138, USA., Frank-Kamenetsky M; Wave Life Sciences, Cambridge, MA 02138, USA., Maguire A; Wave Life Sciences, Cambridge, MA 02138, USA., Tseng WC; Wave Life Sciences, Cambridge, MA 02138, USA., Taborn K; Wave Life Sciences, Cambridge, MA 02138, USA., Kothari N; Wave Life Sciences, Cambridge, MA 02138, USA., Akhtar A; Wave Life Sciences, Cambridge, MA 02138, USA., Bowman K; Wave Life Sciences, Cambridge, MA 02138, USA., Shelke JD; Wave Life Sciences, Cambridge, MA 02138, USA., Lamattina A; Wave Life Sciences, Cambridge, MA 02138, USA., Hu XS; Wave Life Sciences, Cambridge, MA 02138, USA., Jang HG; Wave Life Sciences, Cambridge, MA 02138, USA., Kandasamy P; Wave Life Sciences, Cambridge, MA 02138, USA., Liu F; Wave Life Sciences, Cambridge, MA 02138, USA., Longo K; Wave Life Sciences, Cambridge, MA 02138, USA., Looby R; Wave Life Sciences, Cambridge, MA 02138, USA., Meena; Wave Life Sciences, Cambridge, MA 02138, USA., Metterville J; Wave Life Sciences, Cambridge, MA 02138, USA., Pan Q; Wave Life Sciences, Cambridge, MA 02138, USA., Purcell-Estabrook E; Wave Life Sciences, Cambridge, MA 02138, USA., Shimizu M; Wave Life Sciences, Cambridge, MA 02138, USA., Prakasha PS; Wave Life Sciences, Cambridge, MA 02138, USA., Standley S; Wave Life Sciences, Cambridge, MA 02138, USA., Upadhyay H; Wave Life Sciences, Cambridge, MA 02138, USA., Yang H; Wave Life Sciences, Cambridge, MA 02138, USA., Yin Y; Wave Life Sciences, Cambridge, MA 02138, USA., Zhao A; Wave Life Sciences, Cambridge, MA 02138, USA., Francis C; Wave Life Sciences, Cambridge, MA 02138, USA., Byrne M; Wave Life Sciences, Cambridge, MA 02138, USA., Dale E; Wave Life Sciences, Cambridge, MA 02138, USA., Verdine GL; Department of Stem Cell and Regenerative Biology, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA., Vargeese C; Wave Life Sciences, Cambridge, MA 02138, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Jun 11; Vol. 35 (3), pp. 102246. Date of Electronic Publication: 2024 Jun 11 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102246
Abstrakt:	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. Competing Interests: N.I., Y.L., M.F.-K., A.M., W.C.T., K.T., N.K., A.A., K.B., J.D.S., A.L., X.S.H., H.G.J., P.K., F.L., K.L., R.L., M., J.M., Q.P., E.P.-E., M.S., P.S.P., S.S., H.Y., A.Z., C.F., M.B., E.D., and C.V. were employees of Wave Life Sciences during the completion of this work. M. is currently an employee of Stoke Therapeutics. G.L.V. is on the board of directors and is a consultant and shareholder for Wave Life Sciences. (© 2024 The Author(s).)
Databáze:	MEDLINE
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