The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy

d’Ydewalle, Constantin; Ramos, Daniel M.; Pyles, Noah J.; Ng, Shi‐Yan; Gorz, Mariusz; Pilato, Celeste M.; Ling, Karen; Kong, Lingling; Ward, Amanda J.; Rubin, Lee L.; Rigo, Frank; Bennett, C. Frank; Sumner, Charlotte J.

doi:10.1016/j.neuron.2016.11.033

Cited by 112 publications

(89 citation statements)

References 99 publications

(115 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of these lncRNAs termed SMN-AS1 is ~1.6 kb long; it starts and finishes within intron 1 (Fig. 1A; [27]). Other one termed SMN-AS1* is ~10 kb long; it starts within intergenic region downstream of exon 8 and extends till intron 5 (Fig.…”

Section: Organization Of Human Smn Genesmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

show abstract

Section: Organization Of Human Smn Genesmentioning

confidence: 99%

“…Exons and introns are shown as boxes and lines, respectively. Loci of antisense RNAs, SMN-AS1 [27], and SMN-AS1* [28] are marked with bars. (B) Diagrammatic representation of human SMN promoter region.…”

Section: Figmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

View full text Add to dashboard Cite

show abstract

“…Furthermore, a long non‐coding RNA that binds to and inhibits the promoter of SMA2 was identified and could efficiently be blocked by an ASO to increase the expression of this gene, suggesting a combination of two ASOs may be another useful strategy in this disease (d' Ydewalle et al . ).…”

Section: Therapeutic Modalitiesmentioning

confidence: 97%

Models for discovery of targeted therapy in genetic epileptic encephalopathies

Maljevic

Reid

Petrou

2017

Journal of Neurochemistry

View full text Add to dashboard Cite

Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.

show abstract

“…In addition, there are several other promising ASO targets within the SMN2 pre-mRNA, such as ISS-N2 deep within intron 7 [38], Element 1 within intron 6 [27, 67] and a GC-rich sequence that partially overlaps ISS-N1 [68, 69]. A recent report showed utility of an ASO targeting an antisense sequence of SMN2 [70]. In cell-based assays, a dual-masking ASO has shown a better efficacy than an ISS-N1 targeting ASO [71].…”

Section: Clinical Development Of Spinraza™ For the Treatment Of Smamentioning

confidence: 99%

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

Ottesen

2017

Translational Neuroscience

140

View full text Add to dashboard Cite

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.

show abstract

The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy

Cited by 112 publications

References 99 publications

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Models for discovery of targeted therapy in genetic epileptic encephalopathies

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

Contact Info

Product

Resources

About