Modified and stabilized gdf propeptides and uses thereof
Abstract
Modified and stabilized propeptides of Growth Differentiation Factor proteins, such as GDF-8 and Bone Morphogenetic Protein-11, are disclosed. Also disclosed are methods for making and using the modified propeptides to prevent or treat human or animal disorders in which an increase in muscle tissue would be therapeutically beneficial. Such disorders include muscle or neuromuscular disorders (such as amyotrophic lateral sclerosis, muscular dystrophy, muscle atrophy, congestive obstructive pulmonary disease, muscle wasting syndrome, sarcopenia, or cachexia), metabolic diseases or disorders (such as such as type 2 diabetes, noninsulin-dependent diabetes mellitus, hyperglycemia, or obesity), adipose tissue disorders (such as obesity), and bone degenerative diseases (such as osteoporosis).
Claims
exact text as granted — not AI-modified1 - 118 . (canceled)
119 . A modified GDF-8 propeptide polypeptide comprising a mutation at a corresponding position in the amino acid sequence of SEQ ID NO:1 selected from among the group consisting of Arg-45, Gln-46, Lys-49, Ser-50, Arg-52, Ile-53, Lys-63, Leu-64, Arg-65, Leu-66, Arg-98, and Asp-99.
120 . The modified GDF-8 propeptide polypeptide of claim 1 , wherein the mutation is a substitution mutation with any other amino acid.
121 . The modified GDF-8 propeptide polypeptide of claim 120 , wherein the native amino acid is substituted with alanine.
122 . The modified GDF-8 propeptide polypeptide of claim 120 fused with a different polypeptide.
123 . The modified GDF-8 propeptide polypeptide of claim 122 , further comprising a linker positioned between the modified GDF-8 propeptide polypeptide and different polypeptide.
124 . The modified GDF-8 propeptide polypeptide of claim 122 , wherein the different polypeptide is an IgG Fc domain or fragment thereof.
125 . The modified GDF-8 propeptide polypeptide of claim 122 , wherein the different polypeptide is albumin or fragment thereof.
126 . The modified GDF-8 propeptide polypeptide of claim 120 wherein said GDF-8 propeptide polypeptide is at least 80% identical to the amino acid sequence of SEQ ID NO:5.
127 . The modified GDF-8 propeptide polypeptide of claim 119 wherein said GDF-8 propeptide polypeptide is at least 85% identical to the amino acid sequence of SEQ ID NO:5.
128 . The modified GDF-8 propeptide polypeptide of claim 119 wherein said GDF-8 propeptide polypeptide is at least 90% identical to the amino acid sequence of SEQ ID NO:5.
129 . The modified GDF-8 propeptide polypeptide of claim 119 wherein said GDF-8 propeptide polypeptide is at least 95% identical to the amino acid sequence of SEQ ID NO:5.
130 . The modified GDF-8 propeptide polypeptide of claim 124 , wherein the IgG Fc domain or fragment thereof is positioned amino-terminal to the GDF-8 propeptide polypeptide.
131 . The modified GDF-8 propeptide polypeptide of claim 124 , wherein the IgG Fc domain or fragment thereof is positioned carboxy-terminal to the GDF-8 propeptide polypeptide.
132 . The modified GDF-8 propeptide polypeptide of claim 125 , wherein the albumin or fragment thereof is positioned amino-terminal to the GDF-8 propeptide polypeptide.
133 . The modified GDF-8 propeptide polypeptide of claim 125 , wherein the albumin or fragment thereof is positioned carboxy-terminal to the GDF-8 propeptide polypeptide.
134 . A nucleic acid encoding the modified GDF-8 propeptide polypeptide of claim 1 .
135 . A method of treating a disorder by administering a therapeutically effective amount of the modified GDF-8 propeptide of claim 1 , wherein said disorder is selected from among the group consisting of a muscular disorder, a neuromuscular disorder, a metabolic disorder, an adipose tissue disorder, and a bone disorder.Cited by (0)
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