Compositions for improving cell viability and methods of use thereof
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Assignees
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Publication Number
US-11071742-B2
Publication Date
2021-07-27
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 invention relates to compositions and therapeutic methods for treating a neurodegenerative disease in a subject. The compositions comprise tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), each optionally as a pharmaceutically acceptable salt thereof, and are directed to improving cell viability, including neuronal viability.
The disclosed approach addresses reactive oxygen metabolite-mediated oxidative damage leading to mitochondrial dysfunction and cell death in neurodegenerative disease contexts. The rationale focuses on reducing reactive oxygen metabolite-mediated oxidative damage, regulating redox homeostasis, and reducing mitochondrial dysfunction associated with oxidative stress.
The disclosed concept emphasizes a synergistic protective effect from the combination of TUDCA and PBA species compared to each agent alone. The protective effects are supported by cell viability and cell death outcomes using PrestoBlue and LDH readouts in a hydrogen peroxide-induced peroxide neuronal cell model.
Claims Coverage
The claims cover treatment compositions and pharmaceutical compositions for neurodegenerative disease using TUDCA and 4-PBA, with three main inventive feature clusters: specific ingredient ranges by weight or body weight, and a TUDCA:4-PBA weight ratio limitation.
TUDCA and 4-PBA composition with specified gram ranges
A composition for treating a neurodegenerative disease in a subject comprising about 0.5 g to about 1.5 g of tauroursodeoxycholic acid (TUDCA), or a pharmaceutically acceptable salt thereof, and about 2.5 g to about 3.5 g of 4-phenylbutyric acid (4-PBA), or a pharmaceutically acceptable salt thereof.
TUDCA and 4-PBA pharmaceutical composition with body-weight dose ranges
A pharmaceutical composition for treating a neurodegenerative disease in a subject comprising about 10 mg/kg to about 50 mg/kg of tauroursodeoxycholic acid (TUDCA), or a pharmaceutically acceptable salt thereof, and about 10 mg/kg to about 400 mg/kg of 4-phenylbutyric acid (4-PBA), or a pharmaceutically acceptable salt thereof.
TUDCA to 4-PBA weight ratio of about 1:3
A composition for treating a neurodegenerative disease in a subject comprising tauroursodeoxycholic acid (TUDCA), or a pharmaceutically acceptable salt thereof, and 4-phenylbutyric acid (4-PBA), or a pharmaceutically acceptable salt thereof, wherein the bile acid TUDCA or a pharmaceutically acceptable salt thereof and the 4-PBA or a pharmaceutically acceptable salt thereof have a ratio by weight of about 1:3.
Across the independent claims, the claimed coverage centers on treating neurodegenerative disease by providing compositions containing TUDCA and 4-PBA, with protection anchored in specific quantitative ingredient ranges and in a specific TUDCA:4-PBA weight ratio of about 1:3.
Stated Advantages
Improving cell viability, including neuronal viability, by reducing reactive oxygen metabolite-mediated oxidative damage.
Regulating redox homeostasis.
Reducing mitochondrial dysfunction.
Synergistic (greater-than-additive) protective effect versus each agent alone, as supported by viability and cell death outcomes in a hydrogen peroxide-induced peroxide neuronal cell model.
Documented Applications
Treating a neurodegenerative disease in a subject using compositions containing tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA).
Neurodegenerative disease contexts associated with oxidative stress, including Alzheimer’s disease and amyloidosis involving amyloid beta and phosphorylated tau.
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