Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Clinic for Special Children, Gordonville, Pennsylvania, USA.
Ann Clin Transl Neurol. 2024 Jul;11(7):1868-1878. doi: 10.1002/acn3.52093. Epub 2024 May 31.
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.
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).
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.
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.
比较基因单独治疗（单药治疗）或与 SMN2 扩增剂联合治疗（双药治疗）对 1 型脊髓性肌萎缩症高危儿童的疗效。
18 名存在双等位基因 SMN1 缺失和 2 个 SMN2 拷贝的新生儿进行了预防性单药治疗（n=11）或双药治疗（n=7），并随访了中位数为 3 年。主要结局为独立坐立和行走。生物标志物为连续的肌肉超声（疗效）和感觉动作电位（安全性）。
基因治疗在出生后 7-43 天进行；利司扑兰（n=6）或nusinersen（n=1）的双药治疗在 15-39 天开始。在 18 名入组儿童中，17 名能够坐立，15 名能够行走，44%存在运动延迟（即，未能达到预定的里程碑）。接受双药治疗的儿童更早地能够坐立但不能行走。91%的出生后 60 天内进行的肌肉超声检查正常，但在 3-61 个月时，94%的肌肉超声显示至少一个肌肉群的回声增强和/或肌束颤动；这些变化在单药治疗和双药治疗队列之间无法区分。5 名具有三个 SMN2 拷贝的儿童接受了单药治疗：所有儿童均按时坐立和行走，并且在所有时间点肌肉超声检查均正常。接受双药治疗的儿童无一例出现与治疗相关的不良事件。完成感觉测试的 11 名参与者（包括 6 名接受双药治疗的参与者）均具有完整的腓肠感觉反应。
预防性双药治疗耐受良好，可能对严重脊髓性肌萎缩症高危儿童有一定益处，但不能预防广泛的退行性变化。
