Methods and compositions for inducing differentiation of human brown adipocyte progenitors

Inventors

Boss, Olivier D.

Assignees

Energesis Pharmaceuticals Inc

Abstract

This disclosure relates to compositions and methods for recruiting brown adipocytes in vitro and in vivo from brown adipocyte progenitor cells found in human skeletal muscle. Methods for treating metabolic disease are also provided. Additionally, methods for treating hypothermia are provided. In some embodiments, the brown adipocyte recruiter is a human protein or peptide. In other embodiments the brown adipocyte recruiter may be a non-human protein or peptide. In still other embodiments, the brown adipocyte recruiter is a small molecule or natural product.

Core Innovation

The invention is directed to a method of promoting brown adipogenesis in a subject in need thereof by contacting a cell having a metabolic disorder with an agent selected from fibroblast growth factor (FGF) 7 (FGF7) and stromal cell-derived factor 1 (SDF-1), and then transplanting the contacted cell into the subject. The contacted cell is a BAT progenitor cell isolated from human skeletal muscle, and the approach links the use of selected agents to an increased brown adipogenesis outcome after transplantation.

The method is applied for subjects having a metabolic disorder selected from obesity, type II diabetes, insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, hepatosteatosis, fatty liver, non-alcoholic fatty liver disease, hyperuricemia, polycystic ovarian syndrome, acanthosis nigricans, hyperphagia, triglyceride storage disease, Bardet-Biedl syndrome, Laurence-Moon syndrome, Prader-Willi syndrome, neurodegenerative diseases, and/or Alzheimer's disease. The invention frames recruiting or promoting brown adipocyte formation through agent-contacted, skeletal-muscle-derived BAT progenitor cells for a broad set of metabolic disorder contexts.

The supporting disclosure further characterizes brown adipocyte differentiation using brown-adipocyte markers and brown-adipocyte differentiation readouts, including UCP1 and other brown-adipocyte markers such as FABP4, PPARb2, mtTFA, PGC-1b1, and COX IV. The disclosure describes that the agents induce differentiation and/or UCP1 and other brown-adipocyte markers, providing evidence of brown-adipogenesis in connection with the described recruiter agents and associated marker measurements.

Claims Coverage

The independent claim covers promoting brown adipogenesis in a subject with a metabolic disorder by agent-contacting skeletal-muscle-derived BAT progenitor cells and transplanting the contacted cells. The inventive features are centered on agent selection (FGF7 and SDF-1) and the use of BAT progenitors isolated from human skeletal muscle, with dependent claims further narrowing the progenitor cell definition using immunophenotyping constraints (CD34 and/or CD31).

Overall, the claim coverage centers on a workflow in which skeletal-muscle-derived BAT progenitor cells from human are contacted with FGF7 and/or SDF-1 and then transplanted to promote brown adipogenesis in subjects with specified metabolic disorders. Dependent refinements in the family further restrict the cell population by immunophenotyping requirements (CD34 positivity and/or CD31 negativity).

Stated Advantages

Documented Applications