Beyond motor rescue: defining adequate SMN restoration in spinal muscular atrophy
Crystal Jing Jing Yeo
Crystal Jing Jing Yeo
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Commentary

Beyond motor rescue: defining adequate SMN restoration in spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is characterized by motor neuron degeneration due to deficiency in the survival of motor neuron (SMN) protein. Disease-modifying therapies have transformed outcomes in SMA, while also revealing an increasingly complex spectrum of residual disease biology. In this issue of the JCI, Tapken, Rahmel-Stein, and colleagues demonstrated cell-specific SMN expression and persistent alterations in peripheral immune cell populations in nusinersen- or risdiplam-treated adults with SMA. Their findings extend the question of selective vulnerability beyond motor neurons and raise an increasingly important therapeutic question: What constitutes adequate SMN restoration? This Commentary considers how cell type, developmental timing, SMN requirement, and downstream response may shape treatment-modified SMA, with implications for systemic and CNS-directed therapies.

Authors

Crystal Jing Jing Yeo

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Figure 1

Immune alterations driven by SMN deficiency highlight complexities in long-term outcomes for treatment-modified SMA.

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Immune alterations driven by SMN deficiency highlight complexities in lo...
(A) SMA is a neuromuscular disease caused by pathogenic mutations in the SMN1 gene that lead to SMN deficiency and motor neuron death. The success of gene therapies including nusinersen, risdiplam, and onasemnogene abeparvovec to correct SMN deficiency in motor neurons has profoundly increased survival of patients with SMA. (B) Longer patient lifespans have revealed effects of SMN deficiency that extend beyond the neuromuscular system. Tapken, Rahmel-Stein, and co-authors (4) revealed that SMA was associated with alterations in immune cell populations that persisted after the completion of gene therapy. Their findings suggest that DCs and monocytes may have higher intrinsic requirements for SMN than other immune cells, rendering them more vulnerable to alteration in SMA. The authors’ findings add to the growing interest in extraneuronal phenotypes that may play important roles in long-term outcomes of gene therapy–modified SMA.