A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system.

Autor:	Belgrad J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Tang Q; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Hildebrand S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Summers A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Sapp E; Department of Neurology, Massachusetts General Hospital; Boston, Massachusetts, USA., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., O'Reilly D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Luu E; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Bramato B; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Allen S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Cooper D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Alterman J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Yamada K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., Aronin N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA.; Department of Medicine, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA., DiFiglia M; Department of Neurology, Massachusetts General Hospital; Boston, Massachusetts, USA., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA.; Program in Molecular Medicine, University of Massachusetts Chan Medical School; Worcester, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 19. Date of Electronic Publication: 2023 Dec 19.
DOI:	10.1101/2023.12.19.572404
Abstrakt:	Di-valent short interfering RNA (siRNA) is a promising therapeutic modality that enables sequence-specific modulation of a single target gene in the central nervous system (CNS). To treat complex neurodegenerative disorders, where pathogenesis is driven by multiple genes or pathways, di-valent siRNA must be able to silence multiple target genes simultaneously. Here we present a framework for designing unimolecular "dual-targeting" di-valent siRNAs capable of co-silencing two genes in the CNS. We reconfigured di-valent siRNA - in which two identical, linked siRNAs are made concurrently - to create linear di-valent siRNA - where two siRNAs are made sequentially attached by a covalent linker. This linear configuration, synthesized using commercially available reagents, enables incorporation of two different siRNAs to silence two different targets. We demonstrate that this dual-targeting di-valent siRNA is fully functional in the CNS of mice, supporting at least two months of maximal target silencing. Dual-targeting di-valent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g., Huntington's disease: MSH3 and HTT ; Alzheimer's disease: APOE and JAK1 ) with similar potency to a mixture of single-targeting di-valent siRNAs against each gene. This work potentiates CNS modulation of virtually any pair of disease-related targets using a simple unimolecular siRNA. Competing Interests: CONFLICT OF INTERESTS AK and NA are co-founders, on the scientific advisory board, and hold equities of Atalanta Therapeutics; AK is a founder of Comanche Pharmaceuticals, and on the scientific advisory board of Aldena Therapeutics, AlltRNA, Prime Medicine, and EVOX Therapeutics; NA 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 di-valent siRNA and the methods described in this report.
Databáze:	MEDLINE
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