What did we learn from new treatments in SMA? A narrative review

Abstract

Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by SMN1 gene mutations, leading to inevitable motoneuronal degeneration. The introduction of disease modifying therapies has dramatically altered its natural history, shifting management from palliative to proactive approach. The new phenotypes and differences in treatment response and efficacy, are all contributing to reshape our understanding of the disease itself. This paper aims to analyze the lessons derived from the recent therapeutic advances, focusing on key aspects such as therapeutic windows, impact of early treatment and both disease progression and treatment efficacy modifiers. Ultimately, we also aim to give insights on new models of data analysis being explored to optimize patient trajectories and individualize treatment strategies.

Our experience and the overall review of clinical trials and real-world data confirm that early treatment maximizes motor outcomes, especially when started in the pre-clinical phase of the disease. The significant clinical improvements in symptomatic type I infants treated at different ages has provided evidence of an expanded 'therapeutic window', previously reported as limited to the first few months after birth on the basis of neurophysiological findings. The available data also provide evidence that function at baseline, SMN2 copy number, and age at treatment all appear to represent critical determinants of response. The availability of long-term data is increasingly used to pilot new predictive models to support clinical decision-making and to adapt therapeutic goals based on patient-specific variables.

Keywords: Disease modifying therapies; Functional scales; SMA; SMN2; Trajectories; machine learning.