Advances in Therapeutic Development for Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA.

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

“…Among several hundred targets examined thus far, ISS-N1 remains the most effective target for an ASO-mediated stimulation of SMN2 exon 7 inclusion [89]. Numerous studies employing various mouse models have independently validated the in vivo efficacy of ISS-N1-targeting ASOs [23]. The recently approved ISS-N1-targeting drug for SMA, Nusinersen (synonyms: ISIS-SMN Rx , IONIS-SMN Rx and Spinraza™), is a modified oligonucleotide that carries phosphorothioate backbone and encompasses methoxyethyl modification at the 2′-hydroxyl position of the revealed that the sequence spanning from the 10 th to 24 th positions of intron 7 is highly inhibitory for exon 7 inclusion [85].…”

“…Numerous studies employing various mouse models have independently validated the in vivo efficacy of ISS-N1-targeting ASOs [23]. The recently approved ISS-N1-targeting drug for SMA, Nusinersen (synonyms: ISIS-SMN Rx , IONIS-SMN Rx and Spinraza™), is a modified oligonucleotide that carries phosphorothioate backbone and encompasses methoxyethyl modification at the 2′-hydroxyl position of the sugar moiety [23]. The above-mentioned modifications are known to enhance the in vivo stability of oligonucleotides.…”

“…Aberrant expression and/or localization of SMN have been associated with several other diseases, including amyotrophic lateral sclerosis (ALS), metabolic disorders, male infertility, and stress-associated disorders [14, 20–22]. Correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in mouse models of SMA [23, 24]. The first approved drug for SMA, Nusinersen (Spinraza™), is an antisense oligonucleotide (ASO) that promotes inclusion of SMN2 exon 7 by sequestering an inhibitory cis -element called Intronic Splicing Silencer N1 or ISS-N1 [25, 26].…”

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

“…These crucial findings, together with others, suggest that astrocytes, sensory neurons, Schwann cells and skeletal muscle may all contribute to the expression of the disease and its associated motor neuron loss [28,29,27,30,25,31,32]. Additional evidence of the potential key role of non–motor neuronal cells in SMA pathogenesis was recently provided by an effort to up-regulate SMN protein, introducing the wild-type SMN1 gene [33-36], or by modulating SMN2 splicing with oligonucleotides or small molecules in mice (for review see [4], [37,38]. Several recent studies have demonstrated that these strategies can significantly increase survival of SMA mice [39-44,38].…”

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

“…Here we describe an example of ASO-mediated splicing correction in Spinal Muscular Atrophy (SMA), a leading genetic cause of infant mortality (31–33). SMA is caused by the loss of the Survival Motor Neuron 1 ( SMN1 ) gene (34).…”