In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.

In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.

In certain aspects, the present invention provides compositions and methods for modulating (promoting or inhibiting) growth of a tissue, such as bone, cartilage, muscle, fat, brown fat and/or neuronal tissue and for treating metabolic disorders such as diabetes and obesity, as well as disorders associated with any of the foregoing tissue.

The present disclosure provides compositions and methods for treating or preventing ulcers in subjects having low red blood cell levels and/or hemoglobin levels (e.g, anemia). In some embodiments, the compositions of the disclosure may be used to treat or prevent ulcers associated with anemia.

Provided herein are methods for treating myeloproliferative neoplasm-associated myelofibrosis in a subject, comprising administering to the subject an ActRIIB signaling inhibitor. Also provided herein are methods for treating myeloproliferative neoplasm-associated myelofibrosis in a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutically effective amount of an ActRIIB signaling inhibitor, and wherein said treating reduces or palliates one or more symptoms of said myeloproliferative neoplasm-associated myelofibrosis in said subject. Also provided herein is a method for treating anemia in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of an ActRIIB signaling inhibitor, wherein the subject has myeloproliferative neoplasm-associated myelofibrosis.

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.

In certain aspects, the disclosure provides soluble heteromeric polypeptide complexes comprising an extracellular domain of an ALK7 receptor and an extracellular domain of ActRIIB In certain aspects, these ALK7:ActRIIB heteromultimers are can be used to improve metabolic parameters in a patient in need thereof. In certain aspects, these ALK7:ActRIIB heteromultimers are can be used to treat or prevent one or more kidney-associated disease or condition in a patient in need thereof.

In certain aspects, the present invention provides compositions and methods for modulating (promoting or inhibiting) growth of a tissue, such as bone, cartilage, muscle, fat, and/or neuron. The present invention also provides methods of screening compounds that modulate activity of an ActRII protein and/or an ActRII ligand. The compositions and methods provided herein are useful in treating diseases associated with abnormal activity of an ActRII protein and/or an ActRII ligand.

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.

The present invention relates to compositions of recombinant polynucleic acid or RNA constructs comprising a first RNA sequence, a second RNA sequence, and a linker RNA sequence, wherein the linker RNA links the first RNA sequence and the second RNA sequence. In addition, linkers that enhance the cleavage of recombinant RNA constructs are described. Also disclosed herein is the use of the compositions in treating diseases and in modulating expression of two or more genes.