Compositions for improving cell viability and methods of use thereof
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Publication Number
US-10857162-B2
Publication Date
2020-12-08
Expiration Date
Abstract
This invention relates to methods and compositions for use improving cell viability, particularly neural cell viability, and more particularly to methods and compositions for use improving cell viability by reducing reactive oxygen metabolite-mediated oxidative damage in a cell, regulating redox homeostasis in a cell, or reducing mitochondrial dysfunction in a cell. The invention further relates to the administration of the bile acid tauroursodeoxycholic acid (TUDCA) in combination with phenylbutyric Acid (PBA) to improve cell viability, and treat at least one symptom associated with, prevent the time of onset of, or slow the development of a disease related to oxidative stress.
Core Innovation
The patent discloses pharmaceutical compositions and methods to improve neuronal (cell) viability by reducing reactive oxygen metabolite-mediated oxidative damage. The approach regulates redox homeostasis and reduces mitochondrial dysfunction associated with oxidative stress-related neuronal injury.
The central disclosure includes administration of bile acid tauroursodeoxycholic acid (TUDCA) in combination with phenylbutyric acid/phenylbutyrate, including sodium phenylbutyrate (e.g., 4-phenylbutyric acid, 4-PBA) described as an HDAC2 inhibitor. The disclosed concept is directed to treating or delaying neurodegenerative diseases associated with oxidative stress.
In the disclosed context of oxidative stress, the patent describes synergistic (greater-than-additive) protection against hydrogen peroxide-induced neuronal apoptosis. Example results described in the document include increased cell viability (PrestoBlue) and decreased cell death (LDH) for TUDCA plus 4-PBA compared with each agent alone.
Claims Coverage
The independent claim and related dependent claims primarily cover combination treatment of ALS symptoms using TUDCA together with sodium phenylbutyrate, with additional refinements specifying dosing ranges, fixed dosing schedules, oral administration in a single dosage form, treatment duration constraints, and treatment of subjects suspected of ALS.
Treating ALS symptoms with TUDCA and sodium phenylbutyrate within specified body-weight ranges
A method of treating at least one symptom of Amyotrophic Lateral Sclerosis (ALS) in a human subject by administering tauroursodeoxycholic acid (TUDCA) at about 10 mg/kg to about 30 mg/kg of body weight and administering sodium phenylbutyrate at about 30 mg/kg to about 100 mg/kg of body weight.
Refining sodium phenylbutyrate daily dose range
The method includes administering sodium phenylbutyrate at a daily amount of about 0.5 to about 10 grams per day.
Specifying sodium phenylbutyrate dosing as 3 grams twice daily
The method includes administering sodium phenylbutyrate at a dose of 3 grams twice daily.
Oral administration in a single dosage form with specified twice-daily amounts
The method specifies oral administration in a single dosage form of TUDCA at 1 gram twice daily and sodium phenylbutyrate at 3 grams twice daily.
Limiting treatment duration to less than 3 months
The method is carried out by administering TUDCA and sodium phenylbutyrate to a subject for less than 3 months.
Treating suspected ALS
The method is applied to a human subject suspected of having ALS.
The claims cover combination treatment of ALS symptoms using TUDCA together with sodium phenylbutyrate, with dosing ranges, fixed dosing schedules, oral administration in a single dosage form, treatment duration constraints, and treatment of subjects suspected of ALS.
Stated Advantages
Improves neuronal (cell) viability by reducing reactive oxygen metabolite-mediated oxidative damage.
Regulates redox homeostasis.
Reduces mitochondrial dysfunction.
Provides synergistic (greater-than-additive) protection against hydrogen peroxide-induced neuronal apoptosis.
Increases cell viability (PrestoBlue) compared with each agent alone.
Decreases cell death (LDH) compared with each agent alone.
Documented Applications
Treating or delaying neurodegenerative diseases associated with oxidative stress, including Alzheimer's disease, amyloidosis-related pathology, and Amyotrophic Lateral Sclerosis (ALS).
Improving neuronal viability in the context of oxidative stress, including hydrogen peroxide-induced neuronal apoptosis.
Treating at least one symptom of Amyotrophic Lateral Sclerosis (ALS) in a human subject, including subjects suspected of having ALS.
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