Figure 1.

Designing and identification of lead ASO variants targeting the intronic repressor Element1. (a) Schematic representation of the design of various Morpholino-modified ASO targeting the intronic repressor Element1 (E1^MOv01 through E1^MOv12ASO). The design of the previously published E1^MO is illustrated above the E1 repressor region (blue). (b) Severe SMNΔ7 mice showed a range of longevity after injections with various E1^MO oligonucleotides. Kaplan–Meier survival curves were constructed from the various treatment groups following ICV delivery on P1 of each ASO (2 µl of a 40 nmol/l solution). Log-rank (Mantel-Cox) statistics were applied for comparisons between lead candidates (E1^MOv10 and E1^MOv11) where P < 0.0001 compared with SMA noninjected animals (top). Bar graph showing the mean survival for each treatment group where (*) indicates P < 0.05 (bottom). (c) Weight gain of SMNΔ7 mice injected with ASO variants (E1^MOv01 – E1^MOv12). Total body weight was measured daily for all animal groups postinjection. (d) Scatter plot of time-to-right (TTR) performance of mice injected with all the E1^MO variants. A late-stage in disease progression, TTR values are shown for P12. ASO, antisense oligonucleotide; ICV, intracerebroventricular; SMA, spinal muscular atrophy; SMN, survival motor neuron.