The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia.

Autor:	Caffall ZF; Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA., Wilkes BJ; Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA., Hernández-Martinez R; Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA., Rittiner JE; Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA., Fox JT; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Wan KK; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Shipman MK; Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA., Titus SA; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Zhang YQ; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Patnaik S; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Boxer MB; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Shen M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Li Z; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Vaillancourt DE; Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA.; Department of Neurology, Fixel Institute for Neurological Diseases, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA., Calakos N; Department of Neurology, Duke University Medical Center, Durham, NC 27715, USA. nicole.calakos@duke.edu.; Department of Neurobiology, Duke University Medical Center, Durham, NC 27715, USA.; Department of Cell Biology, Duke University Medical Center, Durham, NC 27715, USA.; Duke Institute for Brain Sciences, Duke University, Durham, NC 27715, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Aug 18; Vol. 13 (607).
DOI:	10.1126/scitranslmed.abd3904
Abstrakt:	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. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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