ArticleJournal of molecular medicine (Berlin, Germany)2016
Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models.
Article in Journal of molecular medicine (Berlin, Germany), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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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
13 citing papers in PubMed, 19 citations in OpenAlex.
- CDCM: a correlation-dependent connectivity map approach to rapidly screen drugs during outbreaks of infectious diseases.Briefings in bioinformatics · 2024Article
- An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis.Journal of personalized medicine · 2023Review
- A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.International journal of molecular sciences · 2022Article
- Animal Models of Neurodegenerative Disease: Recent Advances in Fly Highlight Innovative Approaches to Drug Discovery.Frontiers in molecular neuroscience · 2022Review
- The Advantages of Connectivity Map Applied in Traditional Chinese Medicine.Frontiers in pharmacology · 2021Review
- Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels.International journal of biological sciences · 2020Article
- A computationally inspired in-vivo approach identifies a link between amygdalar transcriptional heterogeneity, socialization and anxiety.Translational psychiatry · 2019Article
- In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury-Lessons Learned.International journal of molecular sciences · 2019Article
- Considerations for Strategic Use of High-Throughput Transcriptomics Chemical Screening Data in Regulatory Decisions.Current opinion in toxicology · 2019Article
- From gene networks to drugs: systems pharmacology approaches for AUD.Psychopharmacology · 2018Review
- Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
- Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model.PloS one · 2018Article
- Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.Biological psychiatry · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledHuntington's disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low 'hit rates' and limited dimensionality for therapeutic detection. Here, we have employed gene expression microarray analysis of HD samples--a snapshot of the expression of 25,000 genes--to define a gene expression signature for HD from publically available data. We used this information to mine a database for chemicals positively and negatively correlated to the HD gene expression signature using the Connectivity Map, a tool for comparing large sets of gene expression patterns. Chemicals with negatively correlated expression profiles were highly enriched for protective characteristics against mutant HTT fragment toxicity in in vitro and in vivo models. This study demonstrates the potential of using gene expression to mine chemical activity, guide chemical screening, and detect potential novel therapeutic compounds. KEY MESSAGES: Single-endpoint chemical screens have low therapeutic discovery hit-rates. In the context of HD, we guided a chemical screen using gene expression data. The resulting chemicals were highly enriched for suppressors of mutant HTT fragment toxicity. This study provides a proof of concept for wider usage in all chemical screening.
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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.