Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration

Figures

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  Fig 1. SMN levels in brain, spinal cord, liver and quadriceps muscle at P12 and P90. SMN levels were compared between ASO-treated SMA mice and untreated SMA, ASO-treated Het mice, and untreated Het mice. At P12, SMN levels were increased in ASO-SMA mice (n = 12) in all tissues compared with SMA mice (n = 13). SMN levels were decreased in ASO-SMA mice compared with ASO-Het (n = 10) and Het (n = 5) for all tissues except for spinal cord for which there was not significant difference between ASO-SMA and Het. At P90, SMN levels in ASO-SMA (n = 12) were diminished in all tissues compared with ASO-Het (n = 7) and Het (n = 8) animals except spinal cord for which there was no significant difference between ASO-SMA and controls. (Note the different scale for P12 versus P90 SMN levels).

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  Fig 2. Whole blood SMN levels at P12, P30, and P90. SMN levels were between ASO-treated SMA mice and untreated SMA, ASO-treated Het mice, and untreated Het mice. At P12, SMN levels were increased in ASO-SMA mice (n = 11) compared to SMA mice (n = 13) but reduced compared to ASO-Het (n = 10) and Het mice (n = 4). Untreated SMA mice have a mean survival of ~2 weeks. Therefore no SMA disease control animals are available for comparison at P30 or P90. At P30 SMN levels were diminished in ASO-SMA mice (n = 10) compared to ASO-Het (n = 5) and Het (n = 8) mice. At P90, SMN levels in ASO-SMA mice (n = 11) were reduced compared with ASO-Het (n = 6) but not Het (n = 8) mice. *, p<0.05, ***, p<0.001 (Note the different scale for P12, P30, and P90 SMN levels).

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  Fig 3. SMN-Responsive analytes. Levels of biomarker analytes were compared at P12 in ASO-SMA mice (n = 12), in SMA mice (n = 13), ASO-Het (n = 10), and Het mice (n = 5). ASO-Het mice were considered controls for statistical comparison using One-way ANOVA and Dunnett's multiple comparisons test (GraphPad Prism, La Jolla CA). Statistical differences between cohorts and controls are shown as * <0.05, ** <0.01, *** <0.001.

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  Fig 4. Analytes that are not responsive to SMN. ASO-Het mice were considered controls for statistical comparison using One-way ANOVA and Dunnett's multiple comparisons test (GraphPad Prism, La Jolla CA). COMP was significantly reduced in ASO-SMA (n = 12) and SMA (n = 13) compared with ASO-Het (n = 10). There was no significant difference between Het (n = 5) and ASO-Het mice for COMP. AXL and CHI3LI were unchanged in all groups compared with ASO-Het mice. ** <0.01, *** <0.001.

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  Fig 5. Longitudinal electrophysiology. At P12 CMAP amplitude is reduced in ASO-SMA mice (n = 5) compared with ASO-Het (n = 8) (p = 0.045). Otherwise there are no statistically significant differences. Compound muscle action potential, CMAP; motor unit number estimation, MUNE; and average Single Motor Unit Potential, SMUP.

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  Fig 6. Longitudinal Measures of SMN-corrected biomarkers. DPPIV and fetuin A showed no statistically significant change compared to ASO-Het and Het mice at either P30 or P90. The other 3 analytes, tetranectin, osteopontin, and vitronectin, showed no change at P30 but were all altered at P90. * <0.05, ** <0.01.