Treatment for Wolfram syndrome and other endoplasmic reticulum stress disorders
Inventors
Urano, Fumihiko • Mahadevan, Jana • Clark, Amy • Jadhav, Ajit • Maloney, David • Harvey, Brandon • Yang, Shyh-Ming • Henderson, Mark
Assignees
Washington University in St Louis WUSTL • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-11426415-B2
Publication Date
2022-08-30
Expiration Date
2038-03-06
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Abstract
The present invention generally relates to compositions and methods for treating or preventing an endoplasmic reticulum stress disorder in subjects, including compositions and methods for treating or preventing Wolfram syndrome. The present invention also relates to methods for treating symptoms of neurodegenerative diseases.
Core Innovation
The invention relates to compositions and methods for treating or preventing endoplasmic reticulum (ER) stress disorders, specifically including Wolfram syndrome. The treatments involve administering therapeutically effective amounts of JTV519, oxidized JTV519, their salts, esters, or mixtures thereof to subjects in need, addressing the cellular and clinical manifestations of these ER stress disorders.
Wolfram syndrome is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, linked to mutations in the WFS1 and WFS2 genes. These mutations cause β cell and neuronal death through ER and mitochondrial dysfunction, leading to ER stress. The ER is responsible for protein folding, modification, calcium homeostasis, and other vital cellular functions. Disturbances in ER homeostasis trigger the unfolded protein response (UPR), which, if insufficient, activates apoptosis.
The problem addressed by the invention is that ER stress contributes to various diseases including Wolfram syndrome, diabetes, neurodegenerative diseases, and more. Current therapies lack effective targeting of the intracellular mechanisms causing ER stress and cell death. The invention aims to provide therapies that prevent ER calcium leakage and subsequent pathological activation of proteases such as calpain-2, thereby preventing cell death and alleviating symptoms of these diseases.
Claims Coverage
The patent includes one independent claim covering methods of treating or preventing Wolfram syndrome by administering specific pharmaceutical compounds. The coverage focuses on the administration of JTV519 derivatives and combinations with additional agents.
Use of JTV519 and its derivatives for treatment
Administering a therapeutically effective amount of at least one compound selected from JTV519, oxidized JTV519, and their salts and esters to treat or prevent Wolfram syndrome in a subject.
Administration parameters
Administering these compounds at doses ranging from about 0.05 mg to about 100 mg per kg of body weight, via parenteral or oral routes.
Combination therapy with additional active agents
Co-administration with at least one additional active agent such as dantrolene, azumolene, glitazones, GLP-1, sitagliptin, and/or metformin to enhance therapeutic effects.
Treatment of clinical symptoms
The method includes treating clinical symptoms of Wolfram syndrome, specifically β cell and neuronal cell death.
The claims delineate methods for treating Wolfram syndrome by administering JTV519 and related compounds, alone or in combination with other active agents, at specified doses and administration routes, targeting the prevention of clinical symptoms.
Stated Advantages
JTV519 and oxidized JTV519 prevent ER calcium leakage and abnormal activation of calpain-2 in Wolfram syndrome models.
These compounds suppress cell death in β cell models, offering potential to treat ER stress-related cell dysfunction.
JTV519 and derivatives can decrease cytosolic calcium levels, thereby mitigating ER stress responses.
The compounds have good solubility, permeability, and can cross the blood-brain barrier, making them suitable for systemic and neurological applications.
Treatment with JTV519 improves motor function in Wolfram syndrome mouse models.
Documented Applications
Treatment or prevention of Wolfram syndrome in subjects.
Treatment of clinical symptoms associated with ER stress disorders, including β cell and neuronal cell death.
Methods for treating motor dysfunction or improving motor function in subjects with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, prion diseases, and spinocerebellar ataxias.
Treatment or prevention of other ER stress disorders, including Type 1 and Type 2 diabetes, atherosclerosis, inflammatory bowel disease, retinitis pigmentosa, congenital deafness, and idiopathic nephrotic syndrome.
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