Provided herein are methods for the treatment of bone disorders that are associated with kidney disease wherein the methods comprise administration of Activin-ActRIIA inhibitors to a subject in need of the treatment. Also provided herein are methods and compositions for the treatment of low turnover bone disorders wherein the methods comprise administration of Activin-ActRIIA inhibitors to a subject in need of the treatment. Further provided herein are compositions for the treatment of bone disorders that are associated with kidney disease and compositions for the treatment of low turnover bone disorders and vascular calcification.

[0001] This application claims priority to U.S. Provisional Pat. Application No. 61/721,898, filed Nov. 2, 2012, and to U.S. Provisional Pat. Application No. 61/740,665, filed Dec. 21, 2012, the disclosures of each of which are herein incorporated by reference in their entireties.

INTRODUCTION

[0002] Provided herein are methods for the treatment of bone disorders that are associated with kidney disease, such as chronic kidney disease-mineral and bone disorder (“CKD-MBD”), wherein the methods comprise administration of Activin-ActRII inhibitors to a subject in need of the treatment. Also provided herein are methods and compositions for the treatment of low turnover bone disorders wherein the methods comprise administration of Activin-ActRII inhibitors to a subject in need of the treatment. Also provided herein are compositions for the treatment of bone disorders that are associated with kidney disease and compositions for the treatment of low turnover bone disorders and vascular calcification.

BACKGROUND

[0003] Bone growth and mineralization are dependent on the activities of two cell types, osteoclasts and osteoblasts, although chondrocytes and cells of the vasculature also participate in critical aspects of these processes. Developmentally, bone formation occurs through two mechanisms, endochondral ossification and intramembranous ossification, with the former responsible for longitudinal bone formation and the later responsible for the formation of topologically flat bones, such as the bones of the skull. Endochondral ossification requires the sequential formation and degradation of cartilaginous structures in the growth plates that serve as templates for the formation of osteoblasts, osteoclasts, the vasculature and subsequent mineralization. During intramembranous ossification, bone is formed directly in the connective tissues. Both processes require the infiltration of osteoblasts and subsequent matrix deposition.

[0004] Chronic kidney disease is associated with a progressive deterioration in mineral homeostasis, with a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating hormones, such as parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, other vitamin D metabolites, fibroblast growth factor-23, and growth hormone. See, Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group, In: Kidney Int Suppl. (2009) 76 (Suppl 113):S1-130, page S3. The mineral and hormone homeostasis that is disrupted in chronic kidney disease is critical for initial bone formation during growth (bone modeling) and bone structure and function during adulthood (bone remodeling). As a result, bone abnormalities are found in patients with chronic kidney disease. In addition, similarly due to the disruption in mineral and endocrine functions, extraskeletal calcification may be found in patients with chronic kidney disease. These syndromes are termed chronic kidney disease-related mineral and bone disorders (“CDK-MBD”).

[0005] Bone undergoes continuous turnover. Bone turnover is the process of resorption followed by replacement of bone. Osteoblasts and osteoclasts are the cells necessary for bone turnover. Low turnover and adynamic bone diseases are characterized by reduced or absent resorption and replacement of bone. CKD-MBD can be characterized by low turnover or adynamic bone. (Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group, In: Kidney Int Suppl. (2009) 76 (Suppl 113):S1-130, page S34).

[0006] Increased calcium levels in the vasculature can lead to vascular calcification, a condition characterized by increased vessel stiffening. Patients with vascular calcification have an increased risk of myocardial infarction, and vascular calcification is particularly prevalent in patients suffering from kidney disease, e.g., CKD-MBD. See, e.g., Shanahan et al., 2011, Circ. Res. 109:697-711.

[0007] Two related type II receptors, ActRIIA and ActRIIB, have been identified as the type II receptors for activins (Mathews and Vale, 1991, Cell 65:973-982; Attisano et al., 1992, Cell 68: 97-108). Besides activins, ActRIIA and ActRIIB can biochemically interact with several other TGF-beta family proteins, including BMP7, Nodal, GDF8, and GDF11 (Yamashita et al., 1995, J. Cell Biol. 130:217-226; Lee and McPherron, 2001, Proc. Natl. Acad. Sci. 98:9306-9311; Yeo and Whitman, 2001, Mol. Cell 7: 949-957; Oh et al., 2002, Genes Dev. 16:2749-54). ALK4 is the primary type I receptor for activins, particularly for activin A, and ALK-7 may serve as a receptor for activins as well, particularly for activin B.

SUMMARY

[0008] In certain embodiments, provided herein are methods for treating an adynamic bone disorder in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the adynamic bone disorder. Further provided herein are methods for treating an adynamic bone disorder form of CKD-MBD in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the adynamic bone disorder form of CKD-MBD.

[0009] In certain more specific embodiments, the adynamic bone disorder is characterized by absence of tetracycline incorporation into mineralized bone.

[0010] In certain embodiments, provided herein are methods for treating a low bone turnover form of CKD-MBD in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the low bone turnover form of CKD-MBD. In a more specific embodiment, the low bone turnover form of CKD-MBD is osteomalacia.

[0011] In certain embodiments, provided herein are methods for treating a bone disorder characterized by hyperphosphatemia in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the bone disorder characterized by hyperphosphatemia.

[0012] In certain embodiments, provided herein are methods for treating atherosclerotic calcification in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of atherosclerotic calcification.

[0013] In certain embodiments, provided herein are methods for treating a renal disease in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of the renal disease. In a more specific embodiment, the renal disease is renal fibrosis.

[0014] In a specific embodiment, provided herein is a method for treating extraskeletal calcification in a subject, wherein said method comprises administering a therapeutically effective amount of an ActRII inhibitor to the subject. In another specific embodiment, provided herein is a method for preventing extraskeletal calcification in a subject, wherein said method comprises administering a therapeutically effective amount of an ActRII inhibitor to the subject. In specific embodiments, the extraskeletal calcification treated or prevented in a subject by the methods described herein is vascular calcification, i.e., the accumulation of calcium salts in the vasculature of the subject, e.g., calcification of arteries of the subject.

[0015] In certain embodiments, the ActRII inhibitor that can be used with the methods provided herein is a polypeptide comprising an amino acid sequence selected from the group consisting of: 90% identical to SEQ ID NO:2; 95% identical to SEQ ID NO:2; 98% identical to SEQ ID NO:2; SEQ ID NO:2; 90% identical to SEQ ID NO:3; 95% identical to SEQ ID NO:3; 98% identical to SEQ ID NO:3; SEQ ID NO:3; 90% identical to SEQ ID NO:6; 95% identical to SEQ ID NO:6; 98% identical to SEQ ID NO:6; SEQ ID NO:6; 90% identical to SEQ ID NO:7; 95% identical to SEQ ID NO:7; 98% identical to SEQ ID NO:7; SEQ ID NO:7; 90% identical to SEQ ID NO: 12; 95% identical to SEQ ID NO: 12; 98% identical to SEQ ID NO: 12; SEQ ID NO: 12; 90% identical to SEQ ID NO:17; 95% identical to SEQ ID NO:17; 98% identical to SEQ ID NO:17; SEQ ID NO:17; 90% identical to SEQ ID NO:20; 95% identical to SEQ ID NO:20; 98% identical to SEQ ID NO:20; SEQ ID NO:20; 90% identical to SEQ ID NO:21; 95% identical to SEQ ID NO:21; 98% identical to SEQ ID NO:21; and SEQ ID NO:21. In a more specific embodiment, the ActRII inhibitor is a polypeptide comprising the amino acid sequence of SEQ ID NO:7. In a more specific embodiment, the ActRII inhibitor is administered parentally.

[0016] In a specific embodiment, the ActRII inhibitor that can be used with the methods provided herein is an ActRIIA inhibitor, wherein the ActRIIA inhibitor comprises or consists of a polypeptide selected from the group consisting of: a. a polypeptide at least 90% identical to SEQ ID NO:2; b. a polypeptide at least 95% identical to SEQ ID NO:2; c. a polypeptide at least 98% identical to SEQ ID NO:2; d. SEQ ID NO:2; e. a polypeptide at least 90% identical to SEQ ID NO:3; f. a polypeptide at least 95% identical to SEQ ID NO:3; g. a polypeptide at least 98% identical to SEQ ID NO:3; h. SEQ ID NO:3; i. a polypeptide at least 90% identical to SEQ ID NO:6; j. a polypeptide at least 95% identical to SEQ ID NO:6; k. a polypeptide at least 98% identical to SEQ ID NO:6; 1. SEQ ID NO:6; m. a polypeptide at least 90% identical to SEQ ID NO:7; n. a polypeptide at least 95% identical to SEQ ID NO:7; o. a polypeptide at least 98% identical to SEQ ID NO:7; p. SEQ ID NO:7; q. a polypeptide at least 90% identical to SEQ ID NO: 12; r. a polypeptide at least 95% identical to SEQ ID NO: 12; s. a polypeptide at least 98% identical to SEQ ID NO: 12; and t. SEQ ID NO: 12. In a specific embodiment, the ActRIIA inhibitor is a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:7.

[0017] In another specific embodiment, the ActRII inhibitor that can be used with the methods provided herein is an ActRIIB inhibitor, wherein the ActRIIB inhibitor comprises or consists of a polypeptide selected from the group consisting of: a. a polypeptide at least 90% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; b. a polypeptide at least 95% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; c. a polypeptide at least 98% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; d. SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; e. a polypeptide 90% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; f. a polypeptide 95% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; g. a polypeptide 98% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; and h. SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47. In a specific embodiment, the ActRIIB inhibitor is a polypeptide comprising or consisting of SEQ ID NO:23. In another specific embodiment, the ActRIIB inhibitor is a polypeptide comprising or consisting of SEQ ID NO:25.

[0018] In another specific embodiment, an ActRIIA inhibitor and an ActRIIB inhibitor can be used in the methods provided herein (e.g., a composition comprising an ActRIIA inhibitor and an ActRIIB inhibitor can be used; or an ActRIIA inhibitor and an ActRIIB inhibitor can both be administered, separately, to a subject being treated in accordance with the methods described herein), wherein the ActRIIA inhibitor comprises or consists of a polypeptide selected from the group consisting of: a. a polypeptide at least 90% identical to SEQ ID NO:2; b. a polypeptide at least 95% identical to SEQ ID NO:2; c. a polypeptide at least 98% identical to SEQ ID NO:2; d. SEQ ID NO:2; e. a polypeptide at least 90% identical to SEQ ID NO:3; f. a polypeptide at least 95% identical to SEQ ID NO:3; g. a polypeptide at least 98% identical to SEQ ID NO:3; h. SEQ ID NO:3; i. a polypeptide at least 90% identical to SEQ ID NO:6; j. a polypeptide at least 95% identical to SEQ ID NO:6; k. a polypeptide at least 98% identical to SEQ ID NO:6; 1. SEQ ID NO:6; m. a polypeptide at least 90% identical to SEQ ID NO:7; n. a polypeptide at least 95% identical to SEQ ID NO:7; o. a polypeptide at least 98% identical to SEQ ID NO:7; p. SEQ ID NO:7; q. a polypeptide at least 90% identical to SEQ ID NO: 12; r. a polypeptide at least 95% identical to SEQ ID NO: 12; s. a polypeptide at least 98% identical to SEQ ID NO: 12; and t. SEQ ID NO: 12; and wherein the ActRIIB inhibitor comprises or consists of a polypeptide selected from the group consisting of: a. a polypeptide at least 90% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; b. a polypeptide at least 95% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; c. a polypeptide at least 98% identical to SEQ ID NO:17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; d. SEQ ID NO: 17, 18, 23, 26, 27, 29, 30, 31, 32, 33, 36, 37, 42, or 43; e. a polypeptide 90% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; f. a polypeptide 95% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; g. a polypeptide 98% identical to SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47; and h. SEQ ID NO:20, 21, 24, 25, 34, 35, 38, 39, 40, 41, 44, 46, or 47. In a specific embodiment, the ActRIIA inhibitor is a polypeptide comprising or consisting of SEQ ID NO:7 and the ActRIIB inhibitor is a polypeptide comprising or consisting of SEQ ID NO:23. In another specific embodiment, the ActRIIA inhibitor is a polypeptide comprising or consisting of SEQ ID NO:7 and the ActRIIB inhibitor is a polypeptide comprising or consisting of SEQ ID NO:25.

[0019] In certain embodiments, the subject to be treated with the methods provided herein is less than 18 years old. In certain embodiments, the subject to be treated with the methods provided herein has end stage renal disease. In certain embodiments, the subject to be treated with the methods provided herein undergoes dialysis. In certain embodiments, provided herein is a method to increase the height of the subject.

[0020] In certain embodiments, provided herein are methods for treating or preventing hyperphosphatemia, secondary hyperparathyroidism (due to increase in phosphorus), extraskeletal calcification, e.g., vascular calcification, and adynamic bone disorder in a subject, wherein the method comprises administering a therapeutically effective amount of an ActRII inhibitor to a subject in need of treatment of hyperphosphatemia, secondary hyperparathyroidism (due to increase in phosphorus), extraskeletal calcification, e.g., vascular calcification, and adynamic bone.