ArticleMolecular therapy : the journal of the American Society of Gene Therapy2016
Optimization of Morpholino Antisense Oligonucleotides Targeting the Intronic Repressor Element1 in Spinal Muscular Atrophy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 3 of them syntheses that pooled it.
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Who cites it
20 citing papers in PubMed, 3 syntheses or guidelines pooled it, 29 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
- Drug treatment for spinal muscular atrophy types II and III.The Cochrane database of systematic reviews · 2020Pooled it
- Drug treatment for spinal muscular atrophy type I.The Cochrane database of systematic reviews · 2019Pooled it
- Development of 2'-O-Methyl and LNA Antisense Oligonucleotides forBiomedicines · 2023Article
- Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy.Human molecular genetics · 2022Article
- A combinatorial approach increases SMN level in SMA model mice.Human molecular genetics · 2022Article
- Exploring Motor Neuron Diseases Using iPSC Platforms.Stem cells (Dayton, Ohio) · 2022Article
- Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene.Frontiers in molecular biosciences · 2022Review
- Review
- Survival motor neuron deficiency slows myoblast fusion through reduced myomaker and myomixer expression.Journal of cachexia, sarcopenia and muscle · 2021Article
- Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine.Cell reports. Medicine · 2021Review
- RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays.Molecules (Basel, Switzerland) · 2021Review
- The Potential of Induced Pluripotent Stem Cells to Test Gene Therapy Approaches for Neuromuscular and Motor Neuron Disorders.Frontiers in cell and developmental biology · 2021Review
- Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy.Life science alliance · 2021Article
- Spinal Muscular Atrophy Modeling and Treatment Advances by Induced Pluripotent Stem Cells Studies.Stem cell reviews and reports · 2019Review
- Functional characterization of SMN evolution in mouse models of SMA.Scientific reports · 2019Article
- Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.Advances in neurobiology · 2018Review
- Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems.Human genetics · 2017Review
- Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy.JCI insight · 2017Article
- SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy.Human molecular genetics · 2017Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Loss of Survival Motor Neuron-1 (SMN1) causes Spinal Muscular Atrophy, a devastating neurodegenerative disease. SMN2 is a nearly identical copy gene; however SMN2 cannot prevent disease development in the absence of SMN1 since the majority of SMN2-derived transcripts are alternatively spliced, encoding a truncated, unstable protein lacking exon 7. Nevertheless, SMN2 retains the ability to produce low levels of functional protein. Previously we have described a splice-switching Morpholino antisense oligonucleotide (ASO) sequence that targets a potent intronic repressor, Element1 (E1), located upstream of SMN2 exon 7. In this study, we have assessed a novel panel of Morpholino ASOs with the goal of optimizing E1 ASO activity. Screening for efficacy in the SMNΔ7 mouse model, a single ASO variant was more active in vivo compared with the original E1(MO)-ASO. Sequence variant eleven (E1(MOv11)) consistently showed greater efficacy by increasing the lifespan of severe Spinal Muscular Atrophy mice after a single intracerebroventricular injection in the central nervous system, exhibited a strong dose-response across an order of magnitude, and demonstrated excellent target engagement by partially reversing the pathogenic SMN2 splicing event. We conclude that Morpholino modified ASOs are effective in modifying SMN2 splicing and have the potential for future Spinal Muscular Atrophy clinical applications.
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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.