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. 2022 Feb 2;50(10):5401–5423. doi: 10.1093/nar/gkac037

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© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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Figure 4. — Oligonucleotides with chimeric PN-containing backbones have improved potency and durability in CNS. (A) Schematic representation of dosing regimen with black arrow indicating administration of intracerebroventricular dose (day 0, D0) and blue arrow indicating day of analysis (day 7, D7). Relative Malat1 expression (normalized to Hprt1) in spinal cord (left) and cortex (right) one-week post treatment with PBS (beige), stereopure PS oligonucleotide (Malat1-200, light blue) or chimeric PN containing oligonucleotide (Malat1-244, navy blue) at the indicated dose. Data are presented as box and whisker plots with box from min to max with data from individual mice shown, n = 8 * P< 0.05, ** P< 0.01, *** P< 0.001 mixed-effects model with multiple comparisons. (B) Schematic representation of dosing regimen with black arrow indicating administration of ICV dose (day 0, D0) and blue arrow indicating day of analysis (day 28, D28). Relative Malat1 expression (normalized to Hprt1) in spinal cord (top left) and cortex (top right) 4 weeks post treatment with PBS (beige), stereopure PS oligonucleotide (Malat1-200, light blue) or chimeric PN containing oligonucleotide (Malat1-244, navy blue). Concentration of oligonucleotide detected in spinal cord (bottom left) and cortex (bottom right) 4-weeks post treatment with PBS (beige), stereopure PS oligonucleotide (Malat1-200, light blue) or chimeric PN containing oligonucleotide (Malat1-244, navy blue). Data are presented as in panel A, n = 4, **** P< 0.0001 one-way ANOVA with multiple comparisons. (C) Schematic representation of dosing regimen with black arrow indicating administration of intracerebroventricular dose (day 0, D0) and blue arrow indicating day of analysis (day 70, D70). Relative Malat1 expression (normalized to Hprt1) in the indicated tissue in CNS 10-weeks post treatment with PBS (beige), stereopure PS oligonucleotide (Malat1-200, light blue) or chimeric PN containing oligonucleotide (Malat1-244, navy blue). Data are presented as in panel A, n = 3 one-way ANOVA with multiple comparisons. Red asterisks show comparison of MALAT1-244 to PBS; blue asterisks MALAT1-244 to MALAT1-200.