脊髓性肌萎缩症作为神经肌肉疾病精准治疗的蓝图

BACKGROUND: Spinal Muscular Atrophy (SMA) is caused by a deficiency of the survival motor neuron (SMN) protein due to loss of SMN1 and inefficient compensation by SMN2. This genetic architecture has driven the development of precision therapeutics. Over the past decade, SMA management has progressed from supportive care to RNA-based splicing modulation and gene replacement therapy.

METHODS: This review analyzes the evolution of three therapeutic waves in SMA management: antisense oligonucleotides (nusinersen) for SMN2 splicing correction; systemic small-molecule splicing modifiers (risdiplam) addressing SMA as a multisystem disorder; and gene replacement therapy (onasemnogene abeparvovec), including recent intrathecal formulations expanding patient eligibility.

RESULTS: Precision therapies have profoundly altered the disease trajectory, especially when administered presymptomatically. Nusinersen sustains splicing correction, risdiplam restores SMN across central and peripheral tissues, and gene replacement offers durable, one-time genetic correction. However, critical challenges persist regarding therapeutic durability, optimal treatment sequencing, systemic involvement, and long-term safety.

CONCLUSIONS: The evolution of SMA therapies has transformed neurogenetics. Clinical benchmarks have successfully shifted from reactive, symptomatic management to proactive, molecularly targeted precision medicine.