Abstract
OBJECTIVE: Compare efficacy of gene therapy alone (monotherapy) or in combination with an SMN2 augmentation agent (dual therapy) for treatment of children at risk for spinal muscular atrophy type 1. METHODS: Eighteen newborns with biallelic SMN1 deletions and two SMN2 copies were treated preemptively with monotherapy (n = 11) or dual therapy (n = 7) and followed for a median of 3 years. Primary outcomes were independent sitting and walking. Biomarkers were serial muscle ultrasonography (efficacy) and sensory action potentials (safety). RESULTS: Gene therapy was administered by 7-43 postnatal days; dual therapy with risdiplam (n = 6) or nusinersen (n = 1) was started by 15-39 days. Among 18 children enrolled, 17 sat, 15 walked, and 44% had motor delay (i.e., delay or failure to achieve prespecified milestones). Those on dual therapy sat but did not walk at an earlier age. 91% of muscle ultrasounds conducted within 60 postnatal days were normal but by 3-61 months, 94% showed echogenicity and/or fasciculation of at least one muscle group; these changes were indistinguishable between monotherapy and dual therapy cohorts. Five children with three SMN2 copies were treated with monotherapy in parallel: all sat and walked on time and had normal muscle sonograms at all time points. No child on dual therapy experienced treatment-associated adverse events. All 11 participants who completed sensory testing (including six on dual therapy) had intact sural sensory responses. INTERPRETATION: Preemptive dual therapy is well tolerated and may provide modest benefit for children at risk for severe spinal muscular atrophy but does not prevent widespread degenerative changes.