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Publication Number
US-10253319-B2
Publication Date
2019-04-09
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 disclosure describes miRNA-based modulation of thermogenesis as a treatment and prevention approach for obesity. It centers on regulating mitochondrial uncoupling proteins, including UCP1 and UCP2, to influence thermogenesis, and miRNA agents are used to alter expression and/or activity of mitochondrial uncouplers and/or their activators and repressors.
It further describes in silico target-discovery and pathway rationale for miRNA-mediated thermogenesis modulation. The analysis predicts miRNA interactions with thermogenic regulators, cross-references adipocyte miRNAs with a thermogenic target panel, and identifies thermogenic regulators associated with ranked miRNAs, including target lists, binding-site predictions in UCP1 regulatory regions, and pathway and interaction network analyses to support the miRNA selection strategy.
The disclosure also provides miRNA agent compositions, including aptamer-linked aptamirs, for adipose-targeted delivery, and a framework for screening indicator cells for miRNA agents that change thermogenic regulator activity. It includes a multiple microRNAs-one mRNA paradigm centered on UCP1 and UCP2, region-wide binding-site prediction across regulatory regions, seed-overrepresentation analyses, and a multiple miRNA-multiple mRNA association structure including an intronic-miRNA pathway hypothesis involving miR-378 in PPARGC1B and miR-425 in PRDM16.
Claims Coverage
The claim coverage includes one independent claim directed to a method of modulating thermogenesis in a subject by administering an antagomir of miR-22-3p with defined nucleotide-length constraints. The claim set includes three additional inventive features that refine sequence interaction, delivery, and thermogenic targets.
Administering an antagomir of miR-22-3p to modulate thermogenesis
A method for modulating thermogenesis in a subject comprising administering an effective amount of an antagomir of miR-22-3p to the subject.
Antagomir length constraint for miR-22-3p
The antagomir is from 7 to 18 nucleotides in length.
Antagomir binding to the miR-22-3p seed sequence
The antagomir binds to the seed sequence of miR-22-3p.
Antagomir delivered as a liposome or nanoparticle
The antagomir is comprised in a liposome or nanoparticle.
Targeting moiety linked to antagomir binding CD36/FAT/SR-B2
The antagomir is linked to a targeting moiety that specifically binds to CD36/Fatty Acid Transporter (FAT)/SR-B2.
Modulating UCP1 or UCP2 with the antagomir
An antagomir modulates the activity or expression of UCP1 or UCP2.
Overall, the claim coverage focuses on administering a miR-22-3p antagomir of defined length to modulate thermogenesis, with refinements emphasizing seed-sequence binding, delivery in a liposome or nanoparticle, targeting via CD36/FAT/SR-B2, and modulation of UCP1 or UCP2 activity or expression.
Stated Advantages
Documented Applications
Treatment and prevention of obesity by modulating thermogenesis using miRNA agents.
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