ArticleMolecular therapy : the journal of the American Society of Gene Therapy2012
Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Systematic review and meta-analysis determining the benefits of in vivo genetic therapy in spinal muscular atrophy rodent models.Gene therapy · 2022Pooled it
- Pre-mRNA Splicing Modulation by Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Optimization of Bifunctional Antisense Oligonucleotides for Regulation of Mutually Exclusive Alternative Splicing ofMolecules (Basel, Switzerland) · 2022Article
- Targeted-Deletion of a Tiny Sequence via Prime Editing to Restore SMN Expression.International journal of molecular sciences · 2022Article
- Design of Bifunctional Antisense Oligonucleotides for Exon Inclusion.Methods in molecular biology (Clifton, N.J.) · 2022Article
- High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome.International journal of molecular sciences · 2021Article
- RNA in spinal muscular atrophy: therapeutic implications of targeting.Expert opinion on therapeutic targets · 2020Review
- Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons.JCI insight · 2020Article
- Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders.Genes · 2018Review
- Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer.Expert opinion on therapeutic targets · 2018Review
- Pre-mRNA Splicing Modulation by Antisense Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2018Article
- How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.Gene therapy · 2017Review
- Review
- Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.Nucleic acid therapeutics · 2017Article
- Diverse role of survival motor neuron protein.Biochimica et biophysica acta. Gene regulatory mechanisms · 2017Review
- Review
- ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.Translational neuroscience · 2017Article
- Retrotransposons jump into alternative-splicing regulation via a long noncoding RNA.Nature structural & molecular biology · 2016Article
- Optimization of Morpholino Antisense Oligonucleotides Targeting the Intronic Repressor Element1 in Spinal Muscular Atrophy.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of survival motor neuron-1 (SMN1). A nearly identical copy gene, SMN2, is present in all SMA patients. Although the SMN2 coding sequence has the potential to produce full-length SMN, nearly 90% of SMN2-derived transcripts are alternatively spliced and encode a truncated protein. SMN2, however, is an excellent therapeutic target. Previously, we developed antisense-based oligonucleotides (bifunctional RNAs) that specifically recruit SR/SR-like splicing factors and target a negative regulator of SMN2 exon-7 inclusion within intron-6. As a means to optimize the antisense sequence of the bifunctional RNAs, we chose to target a potent intronic repressor downstream of SMN2 exon 7, called intronic splicing silencer N1 (ISS-N1). We developed RNAs that specifically target ISS-N1 and concurrently recruit the modular SR proteins SF2/ASF or hTra2β1. RNAs were directly injected in the brains of SMA mice. Bifunctional RNA injections were able to elicit robust induction of SMN protein in the brain and spinal column of neonatal SMA mice. Importantly, hTra2β1-ISS-N1 and SF2/ASF-ISS-N1 bifunctional RNAs significantly extended lifespan and increased weight in the SMNΔ7 mice. This technology has direct implications for SMA therapy and provides similar therapeutic strategies for other diseases caused by aberrant splicing.
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