Abstract: The invention features polypeptides that include an extracellular ActRIIB variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIB variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), fibrosis, and/or pulmonary hypertension.

Abstract: The invention relates to methods of treating functional iron deficiency (FID) associated with low, very low, or intermediate risk myelodysplastic syndromes. FID associated with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF), and FID associated with myelodysplastic syndromes/myeloproliferative neoplasm (MPN) overlap syndromes using small molecule ALK2 inhibitors.

Abstract: The invention features methods of treating a subject receiving a cytopenia-associated myelofibrosis treatment by co-administering an activin receptor type II (ActRII) signaling inhibitor. The ActRII signaling inhibitor may be an antibody that binds to an ActRII ligand, an ActRII antibody, or an ActRII ligand trap.

Abstract: The invention features polypeptides that include an extracellular ActRII chimera. In some embodiments, a polypeptide of the invention includes an extracellular ActRII chimera fused to an Fc domain or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness or atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), low platelet levels (e.g., thrombocytopenia), low neutrophil levels (e.g., neutropenia), fibrosis, metabolic disorders, pulmonary hypertension, and/or diseases and conditions that can be treated with erythropoietin or an erythropoiesis-stimulating agent.

Abstract: The invention features methods of treating a subject having a cytopenia associated with a myelodysplastic syndrome, a cytopenia associated with chronic myelomonocytic leukemia, or a cytopenia associated with myelofibrosis, such as anemia, thrombocytopenia, or neutropenia, by administering to the subject an ActRII signaling inhibitor, such as an ActRIIA ligand trap including an extracellular ActRIIA variant. The extracellular ActRIIA variant may be fused to an Fc domain or moiety.

Abstract: The present invention relates to compositions and methods of GDNF fusion polypeptides, wherein the GDNF fusion polypeptides include an Fc domain, an albumin-binding peptide, a fibronectin domain, or a human serum albumin, joined to a GDNF variant either directly or by the way of a linker. The GDNF fusion polypeptides may used to treat metabolic diseases, such as obesity and Type-1 and Type-2 diabetes, and neurological diseases, such as Amyotrophic lateral sclerosis (ALS) and Parkinson's disease.

Abstract: The invention features polypeptides that include an extracellular ActRIIB variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIB variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), fibrosis, and/or pulmonary hypertension.

Abstract: The present invention relates to compositions and methods of GDNF fusion polypeptides, wherein the GDNF fusion polypeptides include an Fc domain, an albumin-binding peptide, a fibronectin domain, or a human serum albumin, joined to a GDNF variant either directly or by the way of a linker. The GDNF fusion polypeptides may used to treat metabolic diseases, such as obesity and Type-1 and Type-2 diabetes, and neurological diseases, such as Amyotrophic lateral sclerosis (ALS) and Parkinson's disease.

Abstract: The invention features polypeptides that include an extracellular ActRIIa variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIa variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, e.g., Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, inclusion body myositis, amyotrophic lateral sclerosis, sarcopenia; or cancer cachexia; or metabolic diseases, e.g., obesity, Type-1 diabetes, or Type-2 diabetes.

Abstract: The invention features polypeptides that include an extracellular ActRIIB variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIB variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), fibrosis, and/or pulmonary hypertension.

Abstract: The invention features methods of treating iron overload in a subject by administering BMP or hepcidin inhibitors, such as ALK2 inhibitors. The invention also features methods of decreasing iron levels in a subject by administering BMP or hepcidin inhibitors.

Abstract: The invention features methods of treating or preventing the development of a cardiovascular-related disease by administering to the subject a BMP inhibitor or a hepcidin inhibitor, such as an ALK2 inhibitor.

Abstract: The invention features methods of treating or preventing lymphopenia in a subject treated with a BMP inhibitor or a hepcidin inhibitor, such as an ALK2 inhibitor, by co-administering an iron supplement with the inhibitor, and methods of treating a subject who has or is at risk of developing a disease or condition that can be treated with a BMP inhibitor or a hepcidin inhibitor, such as an ALK2 inhibitor, by administering to the subject a BMP inhibitor or a hepcidin inhibitor and an iron supplement.

Abstract: The invention features polypeptides that include an extracellular ActRII variant, such as an ActRIIA variant, ActRIIB variant, or ActRII chimera. In some embodiments, a polypeptide of the invention includes an extracellular ActRII variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions containing said polypeptides and methods of using the polypeptides to treat diseases and conditions that can be treated with erythropoietin or an erythropoiesis-stimulating agent.

Abstract: The invention features polypeptides that include an extracellular ActRIIA variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIA variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions containing said polypeptides and methods of using the polypeptides to treat diseases and conditions including neuromuscular diseases, osteogenesis imperfecta, myelofibrosis, thrombocytopenia, neutropenia, and age-related and treatment-related metabolic disease.

Abstract: The invention features polypeptides that include an extracellular ActRIIa variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIa variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, e.g., Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, inclusion body myositis, amyotrophic lateral sclerosis, sarcopenia; or cancer cachexia; or metabolic diseases, e.g., obesity, Type-1 diabetes, or Type-2 diabetes.

Abstract: The invention features polypeptides that include an extracellular ActRIIB variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRIIB variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions containing said polypeptides and methods of using the polypeptides to treat diseases and conditions including neuromuscular diseases, osteogenesis imperfecta, myelofibrosis, thrombocytopenia, neutropenia, and metabolic disease.

Abstract: The invention features polypeptides that include an extracellular ActRII chimera. In some embodiments, a polypeptide of the invention includes an extracellular ActRII chimera fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving weakness and atrophy of muscles, bone damage, low red blood cell levels (e.g., anemia or blood loss), low platelet levels (e.g., thrombocytopenia), low neutrophil levels (e.g., neutropenia), fibrosis, metabolic disorders, and/or pulmonary hypertension.

Abstract: The invention relates to methods of treating multiple osteochondroma and anemia resulting from iron imbalance using small molecule ALK2 inhibitors.

Abstract: The invention features polypeptides that include an extracellular ActRlla variant. In some embodiments, a polypeptide of the invention includes an extracellular ActRlla variant fused to an Fc domain monomer or moiety. The invention also features pharmaceutical compositions and methods of using the polypeptides to treat diseases and conditions involving bone damage, e.g., primary osteoporosis, secondary osteoporosis, osteopenia, osteopetrosis, fracture, bone cancer or cancer metastasis-related bone loss, Paget's disease, renal osteodystrophy, treatment-related bone loss, diet-related bone loss, bone loss associated with the treatment of obesity, low gravity-related bone loss, or immobility-related bone loss.