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. 2020 Jun 18;5(12):e130574. doi: 10.1172/jci.insight.130574

Figure 5. Phenotypic analysis of AAV9-mediated minor snRNA gene delivery in mouse models of SMA.

Figure 5

(A) AAV-mediated gene delivery of human U11/U12 and U11/U12/U4atac snRNAs prolonged survival of severe SMNΔ7 SMA mice. The Kaplan-Meier survival curve indicates significant life extension for SMNΔ7 SMA mice injected with either AAV9-U11/U12 (orange) or AAV9-U11/U12/U4atac (blue) compared with the untreated SMA mice (red). Unaffected animals (black) and SMA mice injected with AAV9 carrying human full-length SMN (green) were used as a positive control. Healthy littermates were also treated with AAV9-U11/U12 (purple) to test for any potential toxicity of the minor snRNAs. Log-rank Mantel-Cox test (P < 0.0001). (B) The average weight per group is plotted across days for the surviving animals in each cohort. Significant weight gain was observed from P10 through P14 in SMNΔ7 mice injected with AAV9-U11/U12 or AAV9-U11/U12/U4atac relative to untreated SMA mice. Statistical analyses were performed by 2-way ANOVA, where an asterisk denotes significant weight gain difference between snRNAs treated and untreated cohorts (P ≤ 0.03). (C) Scatter plot depicting the percentage weight gained from birth to peak. Analysis of percentage weight gain showed significant improvement in peak weight gain in SMNΔ7 SMA mice injected with AAV9-U11/U12 or AAV9-U11/U12/U4atac relative to untreated SMA mice. Statistics: 1-way ANOVA with Tukey’s post hoc test. (D) Righting reflex measurements. Time-to-right (TTR) measurements were initiated on P6 and recorded along animals’ life span. SMNΔ7 SMA mice injected with AAV9-U11/U12 or AAV9-U11/U12/U4atac showed significantly improved TTR from P12 through P16 relative to untreated SMA mice (P = 0.004; 1-way ANOVA; Tukey’s multiple-comparisons test). *P < 0.05; **P < 0.01; ***P < 0.001; ns, no significance. (E and F) Phenotypic assessment in the intermediate Smn2B/– mouse model after delivery of AAV9 expressing minor splicing snRNAs showed a significant extension in survival (E) and increased weight gain (F). Log-rank Mantel-Cox test (P < 0.0001) for survival measurements.