Methods, compositions and uses thereof for reversing sarcopenia
Inventors
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Assignees
Columbia University in the City of New York • William Marsh Rice University
Member
Rice UniversityRice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
Rice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
Publication Number
US-12215132-B2
Publication Date
2025-02-04
Expiration Date
Abstract
Exemplary methods, compositions and uses thereof can be provided for preventing, reducing and/or treating loss of muscle function. In particular, e.g., it is possible to administer to a subject a pharmaceutical composition comprising a therapeutically effective amount of an agent that enhances Interleukin-6 (IL) release during exercise, and optionally a pharmaceutically acceptable carrier or excipient.
Core Innovation
Exemplary methods, compositions and uses thereof are provided for preventing, reducing and/or treating loss of muscle function by administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an agent that enhances Interleukin-6 (IL) release or activity, e.g., during exercise, and optionally a pharmaceutically acceptable carrier or excipient. The exemplary agent can be an endogenous osteocalcin peptide or an engineered osteocalcin peptide, an IL6-bisphosphonate fusion peptide, and/or a Gprc6a agonist, and can be used in manufacturing a medicament for preventing or treating loss of muscle function. The disclosure also contemplates diagnostic methods based on detection of the level of undercarboxylated/uncarboxylated osteocalcin and methods that modulate Liver Factor 1 signaling for preventing or treating loss of muscle function.
Sarcopenia is described as a muscle disease characterized by the coexistence of two of the following three manifestations: loss of muscle mass, loss of grip strength and/or loss of exercise capacity. Multiple diseases and conditions of varied origin may cause sarcopenia, for example sarcopenia may develop post hip fracture, in cancer, liver cirrhosis, Cushing's disease, Duchene's muscular dystrophy, mitochondrial diseases, kidney failure, diabetes and aging. The background states that there is no approved drug to treat any form of sarcopenia and that prior classes of drugs developed to treat sarcopenia have targeted muscle mass only.
The disclosure presents osteocalcin, a bone-derived hormone, as a therapeutic axis that up-regulates myofiber energetics and is necessary and sufficient for normal exercise capacity through an osteocalcin-interleukin-6 axis. Experimental findings described include that treatment with osteocalcin restored running capacity in a dexamethasone-induced model of sarcopenia where prior candidates increased muscle mass but failed to improve muscle function, and that osteocalcin coordinates the dynamic systemic response to exercise by favoring nutrient uptake and catabolism and by promoting IL-6 release during exercise.
Claims Coverage
The claim set includes one independent claim. The principal inventive feature is a method defined by administering an Interleukin-6-Bisphosphonate fusion peptide as a therapeutically effective agent.
Interleukin-6-Bisphosphonate fusion peptide therapy
Administering to the subject a pharmaceutical composition which comprises a therapeutically effective amount of Interleukin-6-Bisphosphonate fusion peptide.
The independent claim defines a method of reducing loss of muscle function by administering a pharmaceutical composition comprising a therapeutically effective amount of an Interleukin-6-Bisphosphonate fusion peptide; dependent claims specify that the subject can be a human, that the fusion peptide can further reduce loss of muscle mass, and that the composition can further comprise a pharmaceutically acceptable carrier or excipient.
Stated Advantages
Prevention, reduction and/or treatment of loss of muscle function.
May further prevent or treat loss of muscle mass.
Osteocalcin improves exercise capacity where prior classes of drugs increased muscle mass but failed to improve muscle function.
IL6-bisphosphonate fusion peptide may target bone to eliminate off-target effects and lead to physiological release of osteocalcin.
Endogenous osteocalcin is described as safe with no recorded negative side-effects in animal models, and engineered forms may increase half-life and dosing interval.
Documented Applications
Prevention, reduction and/or treatment of loss of muscle function and/or loss of muscle mass in subjects with sarcopenia.
Treatment of loss of muscle function associated with conditions explicitly listed: hip fracture, cancer, liver cirrhosis, Cushing's disease, Duchene's muscular dystrophy, mitochondrial diseases, kidney failure, diabetes and aging.
Use of agents that enhance Interleukin-6 release or activity (including osteocalcin, IL6-bisphosphonate fusion peptide, Gprc6a agonists) in manufacturing a medicament for preventing or treating loss of muscle function.
Diagnostic methods based on determining patient levels or ratios of undercarboxylated/uncarboxylated osteocalcin to diagnose or assess risk for loss of muscle function and/or loss of muscle mass.
Gene therapy approaches delivering a gene encoding osteocalcin or a biologically active fragment or variant thereof for preventing, reducing or treating loss of muscle function.
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