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

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.

Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Caffall, Z. F., Wilkes, B. J., Hernandez-Martinez, R., Rittiner, J. E., Fox, J. T., Wan, K. K., Shipman, M. K., Titus, S. A., Zhang, Y.-Q., Patnaik, S., Hall, M. D., Boxer, M. B., Shen, M., Li, Z., Vaillancourt, D. E., Calakos, N. Tags: Research Articles Source Type: research