Fig. 5. First-in-human treatment with ION363 silences FUS expression, decreases FUS pathology and reverses insolubility of RBPs in an ALS-FUS^P525L patient.

a, Timeline of patient J.H.’s ALSFRS-R scores relative to ION363 infusions. Treatment started with 20 mg of ION363 on day 0 and escalated to 120 mg per dose. A total of 12 infusions was administered. Numbers above open circles indicate ION363 doses in milligrams. b, Anti-ASO immunohistochemical staining of formalin-fixed, paraffin-embedded (FFPE) sections of lumbar spinal cord from a non-ALS control (top) and lumbar (middle) and cervical (bottom) spinal cord from ION363-treated ALS-FUS^P525L patient. Scale bars, 100 µm at ×10 and 20 µm at ×40. c, Immunoblot of brainstem tissue from a non-ALS control, an ALS-FUS^P525L control patient and an ION363-treated patient with ALS-FUS^P525L probed with antibodies against non-overlapping epitopes of FUS. d, Immunoblot of equal volumes of sarkosyl-insoluble fractions from brainstem tissue from a non-ALS control, an ALS-FUS^P525L control patient and an ION363-treated patient with ALS-FUS^P525L probed with antibodies against total FUS (FUS-Proteintech[52-400]), FUS-P525L and other RBPs. e, Immunohistochemical staining of FFPE sections from lumbar spinal cord of a non-ALS control, an ALS-FUS^P525L control patient and an ION363-treated patient with ALS-FUS^P525L with an antibody against total FUS (FUS-Bethyl[400-450]; top) and monoclonal (Mo) P525L-specific antibody reactive to FUS aggregates (bottom). Scale bar, 20 µm.

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