RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.

Autor:	Weiss A; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA., Gilbert JW; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Flores IVR; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Belgrad J; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Ferguson C; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Dogan EO; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA., Wightman N; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA., Mocarski K; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA.; Program in Molecular Medicine, UMass Chan Medical School; Worcester, MA, USA., Echeverria D; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Summers A; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Bramato B; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., McHugh N; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Furgal R; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Yamada N; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Cooper D; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Monopoli K; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Godinho BMDC; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Hassler MR; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Yamada K; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA., Greer P; Program in Molecular Medicine, UMass Chan Medical School; Worcester, MA, USA., Henninger N; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA.; Department of Psychiatry, UMass Chan Medical School; Worcester, MA, USA., Brown RH Jr; Department of Neurology, UMass Chan Medical School; Worcester, MA, USA., Khvorova A; RNA Therapeutics Institute, UMass Chan Medical School; Worcester, MA, USA.; Program in Molecular Medicine, UMass Chan Medical School; Worcester, MA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 25. Date of Electronic Publication: 2024 Jun 25.
DOI:	10.1101/2024.06.20.599943
Abstrakt:	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo . With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo . Administered intraventricularly, di-siRNA SOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders. Competing Interests: Competing interests: AK is a co-founder, on the scientific advisory board, and holds 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; Select authors hold patents or on patent applications relating to the divalent siRNA, SOD1-targeting oligonucleotides, and the methods described in this report. NH received compensation for other services from Myrobalan Inc. and General Dynamics during the conduct of this study, unrelated to the present work.
Databáze:	MEDLINE
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