ArticleScience translational medicine2021
The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Generalized dystonia unraveled: Molecular mechanisms, diagnostic strategies, and treatment paradigms.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
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- Computational drug repurposing: approaches, evaluation of in silico resources and case studies.Nature reviews. Drug discovery · 2025Review
- Non-invasive detection of allele-specific CRISPR-SaCas9-KKH disruption ofMolecular therapy. Nucleic acids · 2025Article
- Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA.Disease models & mechanisms · 2024Article
- The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.Current opinion in neurobiology · 2024Review
- A frameshift mutation in the murinebioRxiv : the preprint server for biology · 2024Article
- The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.The Journal of clinical investigation · 2024Review
- The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice.The Journal of clinical investigation · 2024Article
- Motor deficit and lack of overt dystonia in Dlx conditional Dyt1 knockout mice.Behavioural brain research · 2023Article
- Dystonias: Clinical Recognition and the Role of Additional Diagnostic Testing.Seminars in neurology · 2023Article
- DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery.Dystonia (Lausanne, Switzerland) · 2023Article
- Electrophysiological characterization of the striatal cholinergic interneurons inDystonia (Lausanne, Switzerland) · 2022Article
- DYT-Biomolecules · 2022Article
- Nicotine and the developing brain: Insights from preclinical models.Pharmacology, biochemistry, and behavior · 2022Article
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16 authors at 3 institutions in 1 country.
Funding
Abstract
Dystonias are a group of chronic movement-disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.
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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.