Time Is Motor Neuron: Therapeutic Window and Its Correlation with Pathogenetic Mechanisms in Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of lower motor neurons (MNs) in the spinal cord and brain stem, which results in relentless muscle weakness and wasting, leading to premature death due to respiratory complications. The identification of the specific mutations in the survival motor neuron 1 (SMN1) gene that causes SMA has led to the development of experimental therapeutic strategies to increase SMN protein expression, including antisense oligonucleotides, small molecules, and gene therapy, which have so far shown promising results. The timing of therapeutic intervention is crucial since most of the degeneration in MNs occurs in the first months of life in patients with SMA type 1, which is the most severe and common form of SMA. Nevertheless, a precise temporal window for therapeutic intervention has not yet been identified. Evidence from in vivo studies in mice and large animals suggested that early therapeutic intervention for SMA correlated with better motor performance, longer survival, and, occasionally, rescue of the pathological phenotype. Indeed, the need to compensate for the loss of SMN protein function seemed to diminish during adulthood (even though repair ability after nerve injury remained impaired), suggesting the possibility of tapering the therapy administration late in the disease course. Moreover, recent clinical trials on children afflicted with SMA type 1 have shown a more rapid achievement of motor milestones and diminished disease severity when therapy was administered at an early age and earlier in the disease course. Finally, these results highlight the importance of newborn screening for SMA to facilitate early diagnosis and present the patient with available treatments while they are still in the presymptomatic stage.

Keywords: Antisense oligonucleotides; Gene therapy; SMA; Spinal muscular atrophy; Therapeutic window.