Preventing acute neurotoxicity of CNS therapeutic oligonucleotides with the addition of Ca 2+ and Mg 2+ in the formulation.

Autor:	Miller R; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.; Department of Medicine, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Paquette J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.; Department of Medicine, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Barker A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.; Department of Medicine, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Sapp E; MassGeneral Institute for Neurodegenerative Disease, 114 16 Street, Charlestown, MA 02129, USA., McHugh N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Bramato B; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Yamada N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Alterman J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Echeveria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Yamada K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Watts J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Anaclet C; Department of Neurological Surgery, University of California Davis School of Medicine, Davis, CA 95618, USA., DiFiglia M; MassGeneral Institute for Neurodegenerative Disease, 114 16 Street, Charlestown, MA 02129, USA., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA., Aronin N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.; Department of Medicine, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Oct 15; Vol. 35 (4), pp. 102359. Date of Electronic Publication: 2024 Oct 15 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102359
Abstrakt:	Oligonucleotide therapeutics (ASOs and siRNAs) have been explored for modulation of gene expression in the central nervous system (CNS), with several drugs approved and many in clinical evaluation. Administration of highly concentrated oligonucleotides to the CNS can induce acute neurotoxicity. We demonstrate that delivery of concentrated oligonucleotides to the CSF in awake mice induces acute toxicity, observable within seconds of injection. Electroencephalography and electromyography in awake mice demonstrated seizures. Using ion chromatography, we show that siRNAs can tightly bind Ca 2+ and Mg 2+ up to molar equivalents of the phosphodiester/phosphorothioate bonds independently of the structure or phosphorothioate content. Optimization of the formulation by adding high concentrations (above biological levels) of divalent cations (Ca 2+ alone, Mg 2+ alone, or Ca 2+ and Mg 2+ ) prevents seizures with no impact on the distribution or efficacy of the oligonucleotide. The data here establish the importance of adding Ca 2+ and Mg 2+ to the formulation for the safety of CNS administration of therapeutic oligonucleotides. Competing Interests: A.K. and N.A. are co-founders, on the scientific advisory board, and hold equities of Atalanta Therapeutics. A.K. is a founder of Comanche Pharmaceuticals and on the scientific advisory board of Aldena Therapeutics, AlltRNA, Prime Medicine, and EVOX Therapeutics. N.A. is on the scientific advisory board of the Huntington’s Disease Society of America (HDSA). Select authors hold patents or on patent applications relating to the divalent siRNA and the methods described in this report. (© 2024 The Author(s).)
Databáze:	MEDLINE
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