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Publication Number
US-9803203-B2
Publication Date
2017-10-31
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 described invention modulates thermogenesis as a treatment and prevention approach for obesity and diabetes mellitus by administering an isolated miRNA agent that modulates expression and/or activity of mitochondrial uncouplers and thermogenic regulators. The framework links thermogenesis to mitochondrial uncoupling, including respiratory chain uncoupling proteins, and highlights mitochondrial uncoupling protein regulators such as UCP1 and UCP2. The disclosure also describes pathway-specific miRNAs and optional assessment of uncoupler expression/activity in connection with the thermogenesis modulation strategy.
A central concept is the use of miRNA agents, including miRNA, agomir, and antagomir, that regulate one or more thermogenic regulators. The disclosure describes miRNA agents that can modulate mitochondrial uncoupling proteins via direct binding to mRNA, promoter regions, or UTR regions, including modulation through intermediates such as mitochondrial uncoupler activators or repressors. The disclosure includes mapping of thermogenic regulators to miRNA targets and presents specific interactions for hsa-miR-22 family members, including hsa-miR-22, hsa-miR-22-3p, and hsa-miR-22-5p, with UCP1-pathway elements and KDM3A.
The approach uses integrated bioinformatics tool sets to predict miRNA-target relationships and support selection of pathway-specific miRNAs, together with screening using an indicator cell and measuring activity and/or expression of mitochondrial uncoupling and thermogenic regulators. It describes mapping of miRNA binding sites across UCP1 regulatory elements including 3'UTR, promoter, 5'UTR, and coding regions, and across UCP2 regulatory elements including 3'UTR and 5'UTR. Additional confirmation is described using luciferase reporter assays, expression/profiling readouts, high-content cellular phenotypic screening, high-throughput luciferase/qRT-PCR/proteomics workflows, and in vivo obesity model validation using miRNA mimics/antagomirs and thermogenesis/obesity readouts.
Claims Coverage
The independent claim coverage centers on administering an effective amount of an antagomir of miR-22, including miR-22-3p or miR-22-5p, for treating diabetes mellitus. The claims further refine the method by specifying type 2 diabetes mellitus or early-onset type 2 diabetes mellitus, selecting a human subject who is overweight or obese or predisposed to obesity, and defining mitochondrial uncoupling-related target interactions.
Administering an antagomir of miR-22 for diabetes mellitus treatment
A method for treating diabetes mellitus in a subject by administering an effective amount of an antagomir of miR-22, miR-22-3p or miR-22-5p.
Treating type 2 diabetes mellitus
The method is limited to treating type 2 diabetes mellitus.
Treating early-onset type 2 diabetes mellitus
The method is limited to treating early-onset type 2 diabetes mellitus.
Selecting a human subject based on overweight/obesity or obesity predisposition
The method includes treating a human subject who is overweight or obese or who has a genetic or epigenetic predisposition to obesity.
Modulating UCP1 or UCP2 activity or expression using the antagomir
The method includes using an antagomir to modulate the activity or expression of UCP1 or UCP2.
Direct binding to a mitochondrial uncoupler mRNA or promoter region
The miRNA agent directly binds to the mRNA or promoter region of at least one mitochondrial uncoupler.
The claims collectively cover administering an effective amount of an antagomir targeting miR-22 family members to treat diabetes mellitus, with refinements for diabetes subtype and subject population, and with mechanism-defining targeting of mitochondrial uncoupling regulators including UCP1 and UCP2.
Stated Advantages
Documented Applications
RNA-Seq profiling during rosiglitazone- or miRNA-analog-induced differentiation of human pre-adipocytes to evaluate differential mRNA expression and thermogenesis-related uncoupling protein regulation.
High-throughput miRNA target screening using luciferase promoter/3'UTR/enhancer reporter libraries for UCP1, including identification of miRNAs meeting inhibitor/mimic luciferase criteria and subsequent validation logic.
Animal model validation using described diabetes-related mouse models (including DIO and leptin signaling defect models).
Use of extensive nucleic acid sequence listings for human UCP1 and UCP2 transcripts.
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