Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

Abstract

The condition known as 5q spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. It is one of the most common pediatric recessive genetic diseases, and it represents the most common cause of hereditary infant mortality. After decades of intensive basic and clinical research efforts, and improvements in the standard of care, successful therapeutic milestones have been developed, delaying the progression of 5q SMA and increasing patient survival. At the same time, promising data from early-stage clinical trials have indicated that additional therapeutic options are likely to emerge in the near future. Here, we provide updated information on the molecular underpinnings of SMA; we also provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan.

Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases

“…The molecular background of the production of a defective form of SMN protein is a disturbance in the alternate splicing of SMN2 , which results in the production of an isoform of mRNA that has been shortened by one nucleotide (the absence of exon 7) [ 87 , 88 , 89 ]. It is assumed that the silent conversion of cytosine to thymine at position 6 of this exon is crucial in the process, leading to the suppression of the exonic splicing enhancer element (ESE).…”

“…It is assumed that the silent conversion of cytosine to thymine at position 6 of this exon is crucial in the process, leading to the suppression of the exonic splicing enhancer element (ESE). This, in turn, results in the formation of the exonic splicing silencing element (ESS), to which the A1/A2 splicing factor can bind [ 87 , 89 ]. This leads to the translation of the transcript into a dysfunctional SMNΔ7 protein, which is subsequently degraded via a proteasome-associated pathway [ 90 , 91 , 92 , 93 ].…”

“…This leads to the translation of the transcript into a dysfunctional SMNΔ7 protein, which is subsequently degraded via a proteasome-associated pathway [ 90 , 91 , 92 , 93 ]. Accordingly, due to this molecular mechanism, current applied therapies mainly consist of the modification of the splicing phase or the correction of the SMN2 gene in the exon 7 region [ 87 , 88 , 89 ]. The molecular mechanism of SMA is shown in Figure 3 .…”

“…It is the most common type of SMA, reaching about 50–60% of cases [ 90 , 91 ]. The clinical features include difficulty swallowing and sucking, as well as hypotonia and difficulty holding the head [ 87 , 90 , 91 ]. It mainly affects children under 6 months of age [ 90 ].…”

NSC Physiological Features in Spinal Muscular Atrophy: SMN Deficiency Effects on Neurogenesis

“…Type 3 has an onset after 18 months of life and can be divided into 3a, where the patient loses the ability to walk during adulthood, and 3b, where the patient retains the ability to walk; their life span is similar to the general population. Type 4 is so mild that, in many cases, it cannot be diagnosed; its onset is in the second and third decades of life, and patients have a similar walking capacity and life span to the general population [ 1 , 41 , 42 , 43 , 44 ].…”