ArticleNucleic acids research2014
Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain.
Article in Nucleic acids research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice.Nature communications · 2025Article
- Current trends in gene therapy to treat inherited disorders of the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Adeno-Associated Viral Vectors as Versatile Tools for Neurological Disorders: Focus on Delivery Routes and Therapeutic Perspectives.Biomedicines · 2022Review
- Recent advances in molecular therapies for neurological disease: triplet repeat disorders.Human molecular genetics · 2019Review
- The long non-coding RNA NEAT1 is elevated in polyglutamine repeat expansion diseases and protects from disease gene-dependent toxicities.Human molecular genetics · 2018Article
- AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington's Disease Minipig Model.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Review
- Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin.Molecular therapy. Nucleic acids · 2017Article
- RNAi prevents and reverses phenotypes induced by mutant human ataxin-1.Annals of neurology · 2016Article
- Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington's Disease.Molecular therapy. Nucleic acids · 2016Article
- Anti-microRNAs as Novel Therapeutic Agents in the Clinical Management of Alzheimer's Disease.Frontiers in neuroscience · 2016Article
- Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy.Brain : a journal of neurology · 2015Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Huntington's disease is a fatal neurodegenerative disease caused by polyglutamine-expansion in huntingtin (HTT). Recent work showed that gene silencing approaches, including RNA interference (RNAi), improve disease readouts in mice. To advance RNAi to the clinic, we designed miHDS1, with robust knockdown of human HTT and minimized silencing of unintended transcripts. In Rhesus macaque, AAV delivery of miHDS1 to the putamen reduced HTT expression with no adverse effects on neurological status including fine and gross motor skills, no immune activation and no induction of neuropathology out to 6 weeks post injection. Others showed safety of a different HTT-targeting RNAi in monkeys for 6 months. Application of miHDS1 to Huntington's patients requires further safety testing in normal rodents, despite the fact that it was optimized for humans. To satisfy this regulatory requirement, we evaluated normal mice after AAV.miHDS1 injection. In contrast to monkeys, neurological deficits occurred acutely in mice brain and was attributed to off-target silencing through interactions of miHDS1 with the 3'UTR of other transcripts. While we resolved miHDS1 toxicity in mouse brain and maintained miHDS1-silencing efficacy, these studies highlight that optimizing nucleic acid-based medicines for safety in humans presents challenges for safety testing in rodents or other distantly related species.
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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.