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Publication Number
US-9453224-B2
Publication Date
2016-09-27
Expiration Date
Abstract
Provided are novel methods and compositions for the modulation of thermogenesis. Such methods are particularly advantageous in that they allow for the reduction of body fat in a subject without the subject having to adjust their caloric intake through dieting, modify their physical activity or undergo bariatric surgery. Accordingly, the methods of the invention are particularly useful for treating or preventing obesity. Also provided are methods of screening for novel agents that modulate the activity of thermogenic regulators.
Core Innovation
The patent describes miRNA-based modulation of thermogenesis and respiratory chain uncoupling to treat or prevent obesity. It focuses on mitochondrial uncouplers UCP1 and UCP2 as thermogenic regulators whose activity can be modulated in cells and tissues, in particular by using antagomirs directed to miR-22, including miR-22-3p and miR-22-5p.
The disclosed approach uses isolated miRNA agents, including miRNA, agomirs, and antagomirs, to modulate expression and/or activity of thermogenic regulators such as UCP1 and UCP2. Antagomirs are described as modulating activity and/or expression of UCP1 and/or UCP2 in the context of respiratory chain uncoupling and thermogenesis.
The patent also describes miRNA/aptamir compositions for cell/tissue-specific delivery, and it relates molecular targeting concepts to binding-site regions such as 5′UTR, coding sequence, and 3′UTR, as well as promoter regions. It further describes a screening method that identifies miRNA agents that alter thermogenic regulator activity, using indicator cells and ranking or selection based on thermogenic regulators and miRNA-target prediction for UCP1 binding site lists.
Claims Coverage
The partial content identifies two independent claims: one directed to a method of modulating respiratory chain uncoupling in a cell or thermogenesis in a tissue using miR-22 antagomirs acting on UCP1/UCP2, and another directed to reducing body fat in a human subject by administering an effective amount of an miR-22 antagomir that modulates UCP1/UCP2 activity or expression. Across these independent claims, there are 2 main inventive features centered on miR-22 antagomirs and UCP1/UCP2 modulation.
MiR-22 antagomir contact to modulate UCP1 or UCP2 for uncoupling and thermogenesis
A method of modulating respiratory chain uncoupling in a cell or thermogenesis in a tissue by contacting the cell or tissue with an antagomir of miR-22, miR-22-3p or miR-22-5p, wherein the antagomir modulates activity of at least one of UCP1 or UCP2.
Administering miR-22 antagomir to reduce body fat via UCP1 or UCP2 activity or expression
A method of reducing body fat in a human subject in need thereof by administering to the human subject an effective amount of an antagomir of miR-22, miR-22-3p or miR-22-5p, wherein the antagomir modulates activity or expression of at least one of UCP1 or UCP2.
Both independent claims use antagomirs of miR-22, including miR-22-3p and miR-22-5p, to modulate at least one of UCP1 or UCP2, linking modulation of respiratory chain uncoupling and thermogenesis to a method for reducing body fat in a human subject.
Stated Advantages
Treat or prevent obesity by modulating thermogenesis and respiratory chain uncoupling via mitochondrial uncouplers UCP1 and UCP2.
Documented Applications
Reducing body fat in a human subject in need thereof.
Treat or prevent obesity by modulating thermogenesis and respiratory chain uncoupling via mitochondrial uncouplers UCP1 and UCP2.
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