Fig. 5: Stereopure oligonucleotides show durable activity in C9BAC mice. | Nature Communications

Fig. 5: Stereopure oligonucleotides show durable activity in C9BAC mice.

From: Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models

Fig. 5

a Schematic representation of dosing regimen for 8-week study, with mice administered oligonucleotide on days (D) 1 and 8 and evaluated at 2, 4, or 8 weeks. b Relative transcript levels of all variants (top), V3 (middle), or intron 1-containing transcripts (bottom) in cortex (left) or spinal cord (right) at 2-, 4-, and 8-weeks post-dose are shown for C9orf72-631-treated (coral, n = 7) and PBS-treated mice (black, n = 5). C9orf72 transcripts are standardized to Hprt, individual points indicate data from one mouse, and data are presented as mean ± SD. Two-way ANOVA with Sidak’s multiple comparisons. Exact P values are indicated, ns non-significant. c Representative images from evaluation of four mice per treatment group, showing spinal cords of mice treated with C9orf72-631 (top) or PBS (bottom) and stained for RNA foci (Cy3-labeled probe, red), nuclei (DAPI, blue), and motor neurons (anti-NeuN, green). 10 μm scale bars are shown. d Quantification of RNA foci per cell in anterior horn motor neurons in mice treated with PBS (fuschia) or C9orf72-631 (aqua) (Supplementary Fig. 8). e Relative percentage of DPR proteins detected in cortex (left) or spinal cord (right) for PBS (black, n = 5) or C9orf72-631 (coral, n = 7) at 2-, 4- and 8-weeks post-dose. Box plots show minima to maxima with horizontal lines depicting means. Two-way ANOVA with Sidak’s multiple comparisons. f Normalized percentage expression of C9orf72 protein in the spinal cord of wild-type (n = 5) or C9BAC mice treated with PBS (black, n = 4), C9orf-630 (coral, n = 7) or C9orf72-631 (coral, n = 8) at 8 weeks. Data are presented as mean ± SD. Two-way ANOVA with Dunnett’s multiple comparisons. ns, non-significant. Source data are provided as a Source Data file. ASO antisense oligonucleotide, ICV intracerebroventricular, DPR dipeptide-repeat protein; PBS phosphate-buffered saline, All V all variants, WT wild type mice, P probability; polyGP, polyglycine–proline.

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