Compositions and methods for identifying and treating dystonia disorders
Inventors
Calakos, Nicole • Caffall, Zachary F. • Rittiner, Joseph • Shen, Min • Fox, Jennifer T. • Li, Zhuyin
Assignees
Duke University • US Department of Health and Human Services
Publication Number
US-11285142-B2
Publication Date
2022-03-29
Expiration Date
2036-09-29
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Abstract
The present disclosure provides methods and compositions for the treatment, identification, diagnosis, and prognosis of dystonia, or dystonia related disorders.
Core Innovation
The invention provides methods and compositions for the treatment, identification, diagnosis, and prognosis of dystonia and dystonia related disorders. It specifically addresses therapeutic intervention in subjects suffering from dystonia by modulating intracellular signaling pathways, in particular the integrated stress response mediated by eIF2-alpha, to correct cellular phenotypes associated with dystonia, including delta-E Torsin1a mis-localization.
The background identifies dystonia as a movement disorder with limited therapeutic options, where DYT1 early-onset torsion dystonia results from a mutation leading to delta-E Torsin1a, which mis-localizes and disrupts cellular architecture. This mis-localization is an early, robust phenotype suggestive of membrane trafficking defects and potentially targetable molecular pathways.
The invention solves the problem of severe quality of life impairment caused by dystonia coupled with insufficient therapeutic armamentarium. It provides novel approaches to diagnosis and treatment by elucidating the molecular basis of delta-E Torsin1a mis-localization, identifying eIF2-alpha signaling dysfunction, and demonstrating that modulation of this pathway, for example by certain HIV aspartyl protease inhibitors, can normalize Torsin1a mis-localization and improve dystonia-related phenotypes both in vitro and in vivo.
Claims Coverage
The patent presents two independent inventive features encompassing methods of treatment and cellular correction for dystonia involving specific HIV aspartyl protease inhibitors.
Treatment of DYT1 dystonia with HIV aspartyl protease inhibitors
Methods of treating DYT1 dystonia in a subject by administering one or more HIV aspartyl protease inhibitors selected from ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, or combinations thereof.
Correcting delta-E Torsin1A mislocalization using HIV aspartyl protease inhibitors
Methods of correcting delta-E Torsin1A mis-localization in cells by contacting the cell with one or more HIV aspartyl protease inhibitors selected from ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, or combinations thereof.
The claims cover methods of treating DYT1 dystonia and correcting delta-E Torsin1A mis-localization using HIV aspartyl protease inhibitors, specifically naming ritonavir, lopinavir, saquinavir, nelfinavir, and indinavir as active agents.
Stated Advantages
Augmentation of eIF2-alpha signaling normalizes delta-E Torsin1a mis-localization in vitro, providing a non-toxic and efficacious therapeutic target for dystonia.
Pharmacological enhancement of eIF2-alpha phosphorylation improves neonatal survival in a homozygous DYT1 mouse model, demonstrating in vivo therapeutic potential.
The use of HIV aspartyl protease inhibitors corrects Torsin1a localization and secretory deficits with no observed cellular toxicity at effective doses, indicating a novel treatment modality for dystonia.
Overexpression of ATF4, a downstream effector of eIF2-alpha signaling, is sufficient to correct delta-E Torsin1a mis-localization, highlighting therapeutic targets within the pathway.
Modulation of eIF2-alpha pathway restores disrupted synaptic plasticity in DYT1 model mice, indicating correction of brain-specific dysfunction relevant to dystonia pathogenesis.
Documented Applications
Treatment of subjects suffering from dystonia, including DYT1 dystonia, by administering HIV aspartyl protease inhibitors or agents modulating the eIF2-alpha signaling pathway.
Methods for diagnosing, predicting, or monitoring dystonia by detecting biomarkers related to eIF2-alpha pathway components, such as Torsin1a mis-localization, ATF4 expression, or mutations therein.
Pharmacological correction of cellular defects in delta-E Torsin1a mis-localization in patient-derived cells for research or therapeutic screening.
Use in improving neonatal survival in homozygous DYT1 dystonia mouse models through pharmacological modulation of eIF2-alpha signaling.
Restoration of long-term synaptic plasticity in cortico-striatal synapses related to dystonia by modulation of eIF2-alpha pathway activity.
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