ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…Development of antisense oligonucleotides (ASOs) that promote exon 7 inclusion, increase fulllength SMN protein levels (Hua et al 2007), and can rescue severe SMA mice when injected neonatally (Hua et al 2011) thus represents a major therapeutic breakthrough. This technology led to the development of Biogen's Spinraza, the first Food and Drug Administration-approved therapy for SMA (Ottesen 2017), and has increased the hope that ASOs may be successful at mitigating other neurodegenerative diseases.…”

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

“…The above-mentioned modifications are known to enhance the in vivo stability of oligonucleotides. Multiple reports published recently discuss different aspects of the drug development process that led to the FDA approval of Nusinersen [25, 26, 49, 90–93]. More than a dozen independent studies employing ASOs with different chemistries have validated the stimulatory effect of ISS-N1 sequestration on SMN2 exon 7 splicing [89, 94].…”

“…These structures are boxed. Nusinersen and ASO 283–297 are shown as yellow bars [25, 107]. Their annealing positions within intron 7 are indicated.…”

“…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]. In this review, we describe studies that culminated in the discovery of ISS-N1 and analyze how the characterization of ISS-N1 paved the way for a better understanding of pre-mRNA splicing in the context of a human disease.…”

Exploring Multi-Modal Communication Approach for Young Children with Spinal Muscular Atrophy (SMA)

“…Nowadays, SMA affects more than 750,000 patients worldwide and it is the number one genetic killer of infants and toddlers [5]. Unfortunately, there was no effective medical treatment until Nusinersen was approved by the FDA in December 2016 [6]. However, the cost of this treatment is humongous: the first year of treatment will cost $750,000 and $375,000 per year after that [7].…”