ArticleHuman molecular genetics2009
Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 111 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
- Enhanced splicing modulation by NMA-modified antisense oligonucleotides.Nucleic acids research · 2026Article
- Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Strategies for programmable manipulation of alternative splicing.Current opinion in genetics & development · 2024Review
- Optimization of Bifunctional Antisense Oligonucleotides for Regulation of Mutually Exclusive Alternative Splicing ofMolecules (Basel, Switzerland) · 2022Article
- Design of Bifunctional Antisense Oligonucleotides for Exon Inclusion.Methods in molecular biology (Clifton, N.J.) · 2022Article
- History of development of the life-saving drug "Nusinersen" in spinal muscular atrophy.Frontiers in cellular neuroscience · 2022Review
- Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease.Trends in molecular medicine · 2021Review
- Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1.Frontiers in aging neuroscience · 2021Review
- Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.Advances in neurobiology · 2018Review
- Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases.Neuron · 2017Review
- Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease.Molecules (Basel, Switzerland) · 2017Review
- Review
- ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.Translational neuroscience · 2017Article
- 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
- Developing therapies for spinal muscular atrophy.Annals of the New York Academy of Sciences · 2016Review
- Spinal Muscular Atrophy.Neurologic clinics · 2015Review
- Functional correction by antisense therapy of a splicing mutation in the GALT gene.European journal of human genetics : EJHG · 2015Article
- Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions.Annals of the New York Academy of Sciences · 2015Article
- Spinal Muscular Atrophy Therapeutics: Where do we Stand?Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival motor neuron-1 (SMN1). A nearly identical copy gene, SMN2, is present in all SMA patients, which produces low levels of functional protein. Although the SMN2 coding sequence has the potential to produce normal, full-length SMN, approximately 90% of SMN2-derived transcripts are alternatively spliced and encode a truncated protein lacking the final coding exon (exon 7). SMN2, however, is an excellent therapeutic target. Previously, we developed bifunctional RNAs that bound SMN exon 7 and modulated SMN2 splicing. To optimize the efficiency of the bifunctional RNAs, a different antisense target was required. To this end, we genetically verified the identity of a putative intronic repressor and developed bifunctional RNAs that target this sequence. Consequently, there is a 2-fold mechanism of SMN induction: inhibition of the intronic repressor and recruitment of SR proteins via the SR recruitment sequence of the bifunctional RNA. The bifunctional RNAs effectively increased SMN in human primary SMA fibroblasts. Lead candidates were synthesized as 2'-O-methyl RNAs and were directly injected in the central nervous system of SMA mice. Single-RNA injections were able to illicit a robust induction of SMN protein in the brain and throughout the spinal column of neonatal SMA mice. In a severe model of SMA, mean life span was extended following the delivery of bifunctional RNAs. This technology has direct implications for the development of an SMA therapy, but also lends itself to a multitude of diseases caused by aberrant pre-mRNA splicing.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.