A single-cell map of antisense oligonucleotide activity in the brain.

Autor:	Mortberg MA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA., Gentile JE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA., Nadaf N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA., Vanderburg C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA., Simmons S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA., Dubinsky D; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA., Slamin A; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA., Maldonado S; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA., Petersen CL; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA., Jones N; Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA., Kordasiewicz HB; Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA., Zhao HT; Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA., Vallabh SM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA.; McCance Center for Brain Health and Department of Neurology, Massachusetts GeneralHospital, Boston, MA, 02114, USA.; Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA.; Prion Alliance, Cambridge, MA, 02139, USA., Minikel EV; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard,Cambridge, MA, 02142, USA.; McCance Center for Brain Health and Department of Neurology, Massachusetts GeneralHospital, Boston, MA, 02114, USA.; Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA.; Prion Alliance, Cambridge, MA, 02139, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 14. Date of Electronic Publication: 2023 Feb 14.
DOI:	10.1101/2023.02.14.528473
Abstrakt:	Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold the promise of treating myriad brain diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers to inform on drug target engagement. Animal models can link CSF biomarkers to brain parenchyma, but our understanding of how individual cells contribute to bulk tissue signal is limited. Here we employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and macaques treated with an ASO against PRNP . Activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect disease-relevant cells in a neuronal disorder.
Databáze:	MEDLINE
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