ArticleNature communications2021
Small molecule splicing modifiers with systemic HTT-lowering activity.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 85 citations in OpenAlex.
- Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study.British journal of clinical pharmacology · 2024Trial
- Revolutionizing neonatal health: India's journey from assays to advanced genetics.Journal of applied genetics · 2026Review
- The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function.Nature communications · 2026Article
- Specificity and exon target space of splicing modifying compounds.Nature communications · 2026Article
- Depleting prion protein using splice-switching small molecules.bioRxiv : the preprint server for biology · 2026Article
- Framework Nucleic Acids as a Nanocontainer for Delivering Heterogeneous Molecular Drugs.Pharmaceutics · 2026Review
- Effects of High- and Low-Fat Meals on the Bioavailability and Pharmacokinetics of Votoplam, a HTT Gene Splicing Modifier.Clinical pharmacology in drug development · 2026Article
- Unbiased RNA Degrader Identification Uncovers an LC3B-Recruiting Chimera forJournal of the American Chemical Society · 2025Article
- Natural products proposed for the management of Huntington's disease (HD): a comprehensive review.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding.Nature communications · 2025Article
- Review
- Mechanistic studies of small molecule ligands selective to RNA single G bulges.Nucleic acids research · 2025Article
- PRMT5 promotes full-length HTT expression by repressing multiple proximal intronic polyadenylation sites.Nucleic acids research · 2025Article
- Challenges and advances for huntingtin detection in cerebrospinal fluid: in support of relative quantification.Biomarker research · 2025Article
- The Druggable Transcriptome Project: From Chemical Probes to Precision Medicines.Biochemistry · 2025Review
- Artificial intelligence in fracture detection on radiographs: a literature review.Japanese journal of radiology · 2025Review
- RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33.Acta pharmacologica Sinica · 2025Article
- Exploring the therapeutic potential of modulating nonsense-mediated mRNA decay.RNA (New York, N.Y.) · 2025Review
- A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP.Nature communications · 2024Article
- Therapeutic targeting of RNA for neurological and neuromuscular disease.Genes & development · 2024Review
Corrections and comments
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Authors and funding
24 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels.
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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.