Methods and compositions for treating obesity and/or diabetes and for identifying candidate treatment agents
Inventors
Huang, Yadong • Xu, Qin • Mahley, Robert W.
Assignees
Publication Number
US-11376242-B2
Publication Date
2022-07-05
Expiration Date
2037-03-15
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Abstract
Provided are methods and compositions for identifying candidate agents for treatment of obesity, liver disease, and/or diabetes. Such methods include, e.g., contacting a mammalian cell or cell population with a test agent, and measuring an expression level and/or activity level of ClpP in the mammalian cell or in cells of the cell population. Also provided are methods and compositions for treating an individual (e.g., one who is obese and/or has diabetes). Treatment methods include administering an inhibitor of ClpP to the individual (e.g., to prevent or reduce weight gain, to increase insulin sensitivity, and/or to increase glucose tolerance).
Core Innovation
The invention provides methods and compositions for identifying candidate agents for treating obesity, liver disease, and/or diabetes by evaluating their effects on the expression level and/or activity level of ClpP in mammalian cells. The method involves contacting a mammalian cell or cell population with a test agent, measuring the ClpP expression and/or activity level, and determining whether the test agent causes a reduction. Those agents that reduce ClpP expression and/or activity are identified as candidate agents for treatment.
The invention also provides therapeutic methods that involve administering an inhibitor of ClpP to an individual who is obese and/or has diabetes. Treatment with such inhibitors is effective for decreasing fat tissue, preventing or reducing weight gain, increasing insulin sensitivity, and improving glucose tolerance. In some embodiments, the inhibitor is a small molecule such as a β-Lactone or an RNAi or gene editing agent targeting ClpP, which may be administered systemically or locally to achieve liver-specific effects.
The problem being solved is the need for methods and compositions to identify agents that can modulate energy homeostasis and metabolic regulation. Specifically, there is a need for agents that increase insulin sensitivity, prevent or reduce weight gain and fat tissue, and treat obesity, liver disease, and diabetes. Prior to this invention, the physiological functions of ClpP in mitochondria and its role in these metabolic diseases were not well understood, thus lacking targeted therapeutic agents and screening methods.
Claims Coverage
The patent includes one independent claim that defines a method for identifying and treating with candidate agents that inhibit ClpP to address obesity, liver disease, and/or diabetes.
Method of identifying candidate agents by measuring ClpP expression or activity decrease
A method comprising obtaining a reference ClpP expression and/or activity level in mammalian cells from a subject, contacting those cells with a test agent, measuring ClpP expression and/or activity post-contact, and determining a decrease relative to the reference level.
Administering β-Lactone as a ClpP inhibitor for treatment
Administering to the subject the test agent identified as an inhibitor of ClpP, wherein the test agent is a β-Lactone.
Use of various mammalian cells for testing
The method includes use of cells from a mouse, human, and can be performed in vitro, ex vivo, or in vivo, including hepatocytes.
Measurement of ClpP expression at RNA or protein level by standard assays
Measuring ClpP RNA expression via qRT-PCR, microarray, or RNA sequencing, or measuring ClpP protein using anti-ClpP antibody, mass spectrometry, or ELISA.
Measurement of decrease in ClpP expression/activity by 10% or more
The expression and/or activity of ClpP is reduced by at least 10% compared to the reference, indicating candidate agent activity.
Post-administration evaluation of metabolic and physiological parameters
After administering the candidate agent, measuring features including insulin sensitivity, blood glucose, glucose tolerance, body fat mass, adipose tissue amount, white adipose tissue amount, percent fat mass, body weight, adipocyte size, plasma leptin, growth hormone, basal energy expenditure, phosphorylated AKT levels, lean mass, mitochondrial parameters in hepatocytes, fibroblast respiratory capacity, maximal oxygen consumption rate, and resistance to H2O2-induced cytotoxicity.
The independent claim defines a detailed multi-step method that combines screening for ClpP inhibitors by assessing reductions in ClpP activity or expression and subsequent treatment of individuals with such identified candidate agents, particularly β-Lactones, to treat metabolic diseases. The claim covers the use of multiple cell types and includes detailed biochemical measurement techniques as well as in vivo evaluation.
Stated Advantages
Agents that reduce ClpP activity or expression can prevent or reduce weight gain and fat tissue in individuals.
Inhibiting ClpP increases insulin sensitivity and glucose tolerance.
Reduction of ClpP expression specifically in the liver enhances insulin sensitivity without systemic side effects.
Identification of specific β-Lactone small molecule inhibitors of ClpP as potential therapeutics.
Documented Applications
Identifying candidate agents for treating obesity, liver disease, and diabetes by screening for reduction of ClpP expression or activity in mammalian cells.
Treatment of obese and/or diabetic individuals through administration of ClpP inhibitors to decrease fat tissue, reduce weight gain, and improve insulin sensitivity and glucose tolerance.
Use of small molecule β-Lactone inhibitors of ClpP as therapeutic agents.
Targeted liver-specific reduction of ClpP expression to modulate insulin sensitivity.
Screening of test agents in vitro, ex vivo, and in vivo (including rodent and human cells) to discover candidate therapeutic agents for metabolic diseases.
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