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.

Infants Diagnosed with Spinal Muscular Atrophy and 4 SMN2 Copies through Newborn Screening – Opportunity or Burden?

“…It is clearly possible, even likely, that the partial recovery in our patient was due to the early intervention. Experimental data suggest that a partial recovery of motor neurons or motor endplates might be possible if treatment is started early enough [47].…”

“…Since a number of SMN-dependent and SMNindependent therapies are available [11], the timing of treatment is crucial for a good outcome [12,13] and available data show that presymptomatic treatment is superior to treatment after onset of symptoms [14] experts agree that newborn screening should be established [15,[16][17][18][19][20][21][22][23]. Currently first pilot projects for a genetic NBS in SMA are underway [18,[24][25][26][27][28].…”

Synaptotagmin 13 is neuroprotective across motor neuron diseases

“…o Representative image of the performance of an AAV9::Syt13 treated SOD1 G93A mouse in an inverted grid test at P126. Scale bar = 75 µm in b, 100 μm in f, g, and 50 μm in l, m ◂ to supplement SMN as early as possible in the treatment of SMA [25]. In addition, it is possible that increasing only SMN may not completely address the slow neurodegenerative process that causes progressive functional decline beyond childhood in less severe SMA types [6].…”

Spinal muscular atrophy within Amish and Mennonite populations: Ancestral haplotypes and natural history

“…Biallelic deletions of SMN1 cause spinal muscular atrophy (SMA; MIM# 253300), a common monogenic cause of infant mortality characterized by progressive degeneration of lower motor neurons [ 1 – 4 ]. SMN1 encodes survival motor neuron protein (SMN), which is 294 amino acids in length (32 kDa) and interacts with other proteins to influence ribonucleoprotein assembly, ubiquitin homeostasis, cytoskeletal dynamics, endocytosis, and neuromuscular junction stability [ 5 – 7 ].…”