Luteolin for treatment of neuromuscular movement disorder
Inventors
Assignees
Publication Number
US-11844778-B2
Publication Date
2023-12-19
Expiration Date
2042-08-08
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Abstract
Methods for modification of abnormal protein interactions manifested as excessive PACT-mediated PKR activation within cells are described. Methods include administration of luteolin to cells that exhibit dysregulation in PACT-mediated PKR activation. Methods can decrease or prevent excessive non-viral PACT-mediated PKR activation in a cell as may occur due to expression by the cell of a mutant PACT protein. Methods can decrease an abnormal prolonged stress response as may occur in the absence of a stress-inducing activity or agent.
Core Innovation
The invention describes methods for modifying abnormal protein interactions resulting from excessive PACT-mediated PKR activation within cells. This abnormal activation is addressed by administering luteolin to cells experiencing dysregulation in PACT-mediated PKR activation, particularly when the dysregulation is caused by mutations in the PACT protein. Through this approach, the interaction between PACT and PKR proteins in the cell is reduced compared to pretreatment conditions, as shown by lower rates of formation of PACT-PKR heterodimers and PACT-PACT homodimers, as well as increased PACT-TBRP heterodimer formation.
The problem being addressed involves excessive and prolonged activation of the PKR pathway due to mutations in PACT, which disrupts normal cellular stress response regulation. This dysregulation leads to diseases such as dystonia 16 (DYT16), characterized by heightened susceptibility to endoplasmic reticulum (ER) stress, sustained activation of PKR, persistent phosphorylation of eIF2α, and increased apoptosis. Conventional PKR inhibitors are associated with off-target effects and are not well-suited for long-term treatment.
The core innovation provides a method to decrease or prevent excessive non-viral PACT-mediated PKR activation by administration of luteolin, which disrupts pathological PACT interactions and rescues abnormal integrated stress responses in cells. This method is applicable for therapeutic intervention in diseases marked by excessive PACT-mediated PKR activation, including various dystonias and neurodegenerative diseases, and for mitigating abnormal stress responses in the absence of external stress-inducing triggers.
Claims Coverage
The patent contains four independent claims, each defining a main inventive feature related to disruption of PACT-mediated PKR activation, stress response modulation, and luteolin-based therapies.
Disruption of PACT-mediated PKR activation using luteolin
A method is provided in which luteolin is administered to a cell exhibiting dysregulation in PACT-mediated PKR activation. Following administration, the interaction between PACT protein and PKR protein expressed by the cell is decreased compared to the interaction prior to administration.
Decreasing abnormal integrated stress response with luteolin
A method involving determining an initial expression or activity level of a stress biomarker in a cell exhibiting an abnormal integrated stress response, administering luteolin to the cell, and then determining the expression or activity level of the biomarker post-administration. The response is considered decreased when the post-administration level is within about 10% of a normal, non-stress level for the biomarker in the cell.
Treatment of dysregulation in PACT-mediated PKR activation in a subject
A method for treating a subject with dysregulated PACT-mediated PKR activation by administering a composition comprising a therapeutically effective amount of luteolin.
The inventive features claim methods for disrupting pathological protein interactions by administering luteolin to decrease PACT-mediated PKR activation and abnormal integrated stress responses, including treatment methods for subjects affected by such dysregulation.
Stated Advantages
Disclosed methods provide therapeutic benefit for conditions involving excessive PACT-mediated PKR activation, such as dystonias, neurodegenerative diseases, and stress responses in the absence of external triggers.
Luteolin can decrease excessive non-viral PACT-mediated PKR activation without the off-target effects common to known PKR inhibitors, supporting suitability for long-term treatment.
Treatment with luteolin offers benefit both through direct modification of excessive PKR activation and indirect benefit via lower risk of side effects and improved therapeutic value when formulated for bioavailability.
Documented Applications
Therapeutic intervention for dystonias, such as DYT16, including congenital and induced dystonias.
Treatment of diseases characterized by excessive PACT-mediated PKR activation, including Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, prion disease, and Down's Syndrome.
Modification of abnormal stress responses in cells, including in vitro, ex vivo, and in vivo applications for both human and veterinary use.
Preventive therapy in combination with antipsychotic drugs to prevent drug-induced dystonia.
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