FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

Wolfram syndrome is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (also known as DIDMOAD). Insulin dependent diabetes usually occurs as the initial manifestation during the first decade of life, while the diagnosis of Wolfram syndrome is invariably later with onset of the other features in the second and ensuing decades. Two causative genes for this genetic disorder have been identified and are named WFS1 and WFS2. It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through endoplasmic reticulum (ER) and mitochondrial dysfunction. WFS1 gene variants are also associated with a risk of Type 2 diabetes and Type 1 diabetes. Moreover, a specific WFS1 variant can cause autosomal dominant diabetes.

Wolfram syndrome is caused by stress in the ER, a cell component involved in many vital functions of the eyes, brain, and pancreas. The ER is a membrane-bound organelle that is crucial for the folding and maturation of proteins, lipid biosynthesis, and homeostasis of intracellular Ca2+and reduction-oxidation (redox) potential. Protein folding and modification in the ER is highly sensitive to disturbances of ER homeostasis, including altered glycosylation, ER Ca2+depletion, increased mRNA translation, oxidative stress, energy deprivation, metabolic challenge, and inflammatory stimuli. The accumulation of unfolded and misfolded proteins in the ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding and modification, reduces global protein synthesis, and activates ER-associated protein degradation (ERAD). If ER stress is too severe or chronic, or the UPR is compromised and not able to restore the protein folding homeostasis, then numerous apoptotic signaling pathways are activated.

Calpain-2 protease has been found to provide a link between the ER and death of neurons and β cells in Wolfram syndrome. See WO2016/077706 A1, which is hereby incorporated herein by reference. Evidence indicates that ER dysfunction triggers a range of human chronic diseases, including Type 1 and Type 2 diabetes, atherosclerosis, inflammatory bowel disease, retinitis pigmentosa, congenital deafness, idiopathic nephrotic syndrome, and neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Thus, there remains a need for effective therapies targeting the ER for treating Wolfram syndrome and other ER stress disorders.

SUMMARY OF THE INVENTION

Briefly, various aspects of the present invention are directed to methods for treating or preventing an endoplasmic reticulum (ER) stress disorder in a subject in need thereof. The methods comprise administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of JTV519, oxidized JTV519, salts and esters thereof, and mixtures thereof. In further aspects, the present invention is directed to methods for treating or preventing clinical symptoms of an ER stress disorder, such as Wolfram syndrome, in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of JTV519, oxidized JTV519, salts and esters thereof, and mixtures thereof.

In other aspects, the present invention is directed to methods for treating motor dysfunction (e.g., improving motor function) in a subject in need thereof suffering from a neurodegenerative disease comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of JTV519, oxidized JTV519, salts and esters thereof, and mixtures thereof.

Still further aspects of the present invention are directed to various pharmaceutical compositions comprising a therapeutically effective amount of at least one compound selected from the group consisting of JTV519, oxidized JTV519, salts and esters thereof, and mixtures thereof and at least one additional active agent (e.g., dantrolene, azumolene, or pharmaceutically acceptable salts or hydrates thereof).

Other objects and features will be in part apparent and in part pointed out hereinafter.

