ArticleScientific reports2020
Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Mutagenesis-based evolution enables rapid retargeting of l-aptamers for structured RNA recognition.RSC chemical biology · 2026Article
- Cerebellar defects are a primary pathology in mouse models of spinal muscular atrophy.Brain pathology (Zurich, Switzerland) · 2025Article
- Nusinersen corrects L-arginine deficiency in the cerebrospinal fluid of patients with severe spinal muscular atrophy.Neurobiology of disease · 2025Article
- The effect of coadministration of D156844 and AR42 (REC-2282) on the survival and motor phenotype of mice with spinal muscular atrophy.Scientific reports · 2025Article
- SP1-Driven FOXM1 Upregulation Induces Dopaminergic Neuron Injury in Parkinson's Disease.Molecular neurobiology · 2024Article
- Specificity, synergy, and mechanisms of splice-modifying drugs.Nature communications · 2024Article
- Article
- Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy.Nucleic acids research · 2023Article
- Amplifying gene expression with RNA-targeted therapeutics.Nature reviews. Drug discovery · 2023Review
- Exploring Motor Neuron Diseases Using iPSC Platforms.Stem cells (Dayton, Ohio) · 2022Article
- Small molecule splicing modifiers with systemic HTT-lowering activity.Nature communications · 2021Article
- Article
- Regulation of Survival Motor Neuron Gene Expression by Calcium Signaling.International journal of molecular sciences · 2021Article
- Review
- Recognition of single-stranded nucleic acids by small-molecule splicing modulators.Nucleic acids research · 2021Article
- High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome.International journal of molecular sciences · 2021Article
- Review
- Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine.Cell reports. Medicine · 2021Review
- Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease.Trends in molecular medicine · 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
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Nusinersen/SPINRAZA, a splice-switching oligonucleotide that modulates SMN2 (a paralog of SMN1) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule SMN2 splicing modulators such as risdiplam/EVRYSDI and its analog SMN-C3 modulate not only the splicing of SMN2 but also that of secondary splice targets, including forkhead box protein M1 (FOXM1). Through screening SMA patient-derived fibroblasts, a novel small molecule, designated TEC-1, was identified that selectively modulates SMN2 splicing over three secondary splice targets. TEC-1 did not strongly affect the splicing of FOXM1, and unlike risdiplam, did not induce micronucleus formation. In addition, TEC-1 showed higher selectively on galactosylceramidase and huntingtin gene expression compared to previously reported compounds (e.g., SMN-C3) due to off-target effects on cryptic exon inclusion and nonsense-mediated mRNA decay. Moreover, TEC-1 significantly ameliorated the disease phenotype in an SMA murine model in vivo. Thus, TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule drug development with an improved tolerability profile.
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