Engineered osteocalcins for treating sarcopenia

1 . A pharmaceutical composition comprising an engineered osteocalcin peptide with an N-terminal stabilizing mutation that eliminates cleavage by an inactivating protease comprising or consisting of the amino acid sequence of any one of SEQ ID NO: 3 to SEQ ID NO: 11.

2 . The pharmaceutical composition of claim 1 , wherein the engineered osteocalcin peptide is configured to be administered to a subject who suffers from at least one condition selected from the group consisting of hip fracture, cancer, liver cirrhosis, Cushing's disease, Duchenne muscular dystrophy, a mitochondrial disease, kidney failure, diabetes, aging, iatrogenic hypercortisolism, cancer cachexia, cachexia in chronic obstructive pulmonary disease (COPD), rehabilitation from ICU-induced loss in muscle mass and function, Becker muscular dystrophy, spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy, a primary mitochondrial myopathy, fatty acid oxidation disorder (FAOD), Friedreich's ataxia, Charcot-Tooth-Marie disease type 2K, Hereditary spastic paraplegia 7, polymyositis, inclusion body myositis, dermatomyositis, Wilson's disease, Barth syndrome, growth delay-aminoaciduria-cholestasis-iron overload-lactic acidosis-early death (GRACILE) syndrome, Kearns-Sayre syndrome, Leigh syndrome, maternally inherited deafness and diabetes (MIDD), mitochondrial DNA depletion syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS) syndrome, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), mitochondrial Mitochondrial recessive ataxia syndrome (MIRAS), myoclonus epilepsy with ragged red fibers (MERFF), neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and Pearson syndrome.

3 . The pharmaceutical composition of claim 1 , wherein the engineered osteocalcin peptide comprises an Ig Fc region fused to an N-terminus or a C-terminus of the amino acid sequence of any one of SEQ ID NO: 3 to SEQ ID NO: 11.

4 . The pharmaceutical composition of claim 1 , wherein the engineered osteocalcin peptide is a peptide consisting of the amino acid sequence of any one of SEQ ID NO: 3 to SEQ ID NO: 11.

5 . The pharmaceutical composition of claim 1 , wherein the engineered osteocalcin peptide is a peptide comprising or consisting of the amino acid sequence of any one of SEQ ID NO: 4 or SEQ ID NO: 5.

6 . The pharmaceutical composition of claim 1 , wherein the engineered osteocalcin peptide further at least one of prevents, reduces or treats loss of muscle mass.

7 . A method for at least one of preventing, reducing or treating loss of muscle function, comprising: administering to a subject a pharmaceutical composition which comprises a therapeutically effective amount of the pharmaceutical composition of claim 1 .

8 . The method of claim 7 , wherein the subject suffers from sarcopenia.

9 . The method of claim 7 , wherein the subject suffers from at least one condition selected from the group consisting of hip fracture, cancer, liver cirrhosis, Cushing's disease, Duchenne muscular dystrophy, a mitochondrial disease, kidney failure, diabetes, aging, iatrogenic hypercortisolism, cancer cachexia, cachexia in chronic obstructive pulmonary disease (COPD), rehabilitation from ICU-induced loss in muscle mass and function, Becker muscular dystrophy, spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy, primary mitochondrial myopathy, fatty acid oxidation disorder (FAOD), Friedreich's ataxia, Charcot-Tooth-Marie disease type 2K, Hereditary spastic paraplegia 7, polymyositis, inclusion body myositis, dermatomyositis, Wilson's disease, Barth syndrome, growth delay-aminoaciduria-cholestasis-iron overload-lactic acidosis-early death (GRACILE) syndrome, Kearns-Sayre syndrome, Leigh syndrome, maternally inherited deafness and diabetes (MIDD), mitochondrial DNA depletion syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS) syndrome, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), mitochondrial recessive ataxia syndrome (MIRAS), myoclonus epilepsy with ragged red fibers (MERFF), neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and Pearson syndrome.

10 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide with a C-terminal truncation.

11 . The method of claim 7 , wherein the engineered osteocalcin peptide of the pharmaceutical composition comprises an Ig Fc region fused to an N-terminus or a C-terminus of the amino acid sequence of any one of SEQ ID NO: 3 to SEQ ID NO: 11.

12 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1.

13 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 2.

14 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of any one of SEQ ID NO: 12 to SEQ ID NO: 20.

15 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of any one of SEQ ID NO: 21 to SEQ ID NO: 29.

16 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 30.

17 . The method of claim 7 , wherein the pharmaceutical composition further comprises a second engineered osteocalcin peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 31.

18 . The method of claim 7 , wherein the pharmaceutical composition further at least one of prevents, reduces or treats loss of muscle mass.