39 results about "Tgf β superfamily" patented technology

The present invention concerns RPE cells obtainable by directed differentiation from stem cell, particularly, human stem cells. It has been specifically found that culturing stem cells in the presence of one or more member of the TGFβ superfamily, such as Activin A) induced directed differentiation into mature and functional RPE cells. This was evidenced by the expression of markers specific to mature RPE cells, including MiTF-A, RPE65 or Bestrophin). In accordance with one particular embodiment, the cells are a priori cultured with nicotinamide (NA) which was found to augment the cells' response to the inductive effect of the one or more member of the TGFβ superfamily. The invention also provides methods of performing the directed differentiation, as well as methods for use of the resulting RPE cells.

The present invention provides new systems and strategies for the regulation of iron metabolism in mammals. In particular, methods of using agonists and antagonists of TGF-β superfamily members to modulate the expression or activity of hepcidin, a key regulator of iron metabolism, are described. The inventive methods find applications in the treatment of diseases associated with iron overload, such as juvenile hemochromatosis and adult hemochromatosis, and in the treatment of diseases associated with iron deficiency, such as anemia of chronic disease and EPO resistant anemia in end-stage of renal disease. The present invention also relates to screening tools and methods for the development of novel drugs and therapies for treating iron metabolism disorders.

The invention provides hetero-multivalent ligand binging agents (traps) for members of the TGF-β superfamily, as well as methods for making and using such constructs. In an embodiment of the invention there is provided a hetero-multivalent binding agent with affinity for a member of the TGF-β superfamily. The agent comprises the general structure I:(<bd1>-linker1)k-[{<bd1>-linker2-<bd2>-linker3f-}n-(<bd3>)m-(linker4-<bd4>)d]h,where bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for different sites on the same member or for different members of the TGF-β superfamily; at least two of bd1, bd2, bd3, and bd4 are different from each other.

The present invention provides new systems and strategies for the regulation of iron metabolism in mammals. In particular, methods of using agonists and antagonists of TGF-β superfamily members to modulate the expression or activity of hepcidin, a key regulator of iron metabolism, are described. The inventive methods find applications in the treatment of diseases associated with iron overload, such as juvenile hemochromatosis and adult hemochromatosis, and in the treatment of diseases associated with iron deficiency, such as anemia of chronic disease and EPO resistant anemia in end-stage of renal disease. The present invention also relates to screening tools and methods for the development of novel drugs and therapies for treating iron metabolism disorders.

The invention provides multivalent ligand binding agents (traps) for members of the TGF-β superfamily and polypeptide linkers and methods for making and using such constructs. The traps may be used as therapeutic or diagnostic (imaging or non-imaging) agents for diseases / disorders caused by over-production / activity of the target ligand. In an embodiment of the invention there is provided a multivalent binding agent with affinity for a member of the TGF-β superfamily, the agent having the general structure I:(<bd1>-linker1)k-[{<bd1>-linker2-<bd2>linker3f-}n-(<bd3>)m-(linker4-<bd4>)d]h,where:n and h are independently greater than or equal to 1;d, f, m and k are independently equal to or greater than zero;bd1, bd2, bd3 and bd4 are polypeptide binding domains having an affinity for the same member of the TGF-β superfamily, with bd1, bd2, bd3, and bd4 being independently the same or different from each other; and,linker1, linker2, linker3 and linker4 are unstructured polypeptide sequences;wherein the number of amino acids in each linker is determined independently and is greater than or equal to X / 2.5; where,X equals the shortest linear distance between:(a) the C-terminus of an isolated form of the binding domain that is located at the N-terminus of the linker and that is specifically bound to its ligand; and,(b) the N-terminus of an isolated form of the binding domain that is located at the C-terminus of the linker and that is specifically bound to its ligand.

The present invention concerns RPE cells obtainable by directed differentiation from stem cell, particularly, human stem cells. It has been specifically found that culturing stem cells in the presence of one or more member of the TGFβ superfamily, such as Activin A) induced directed differentiation into mature and functional RPE cells. This was evidenced by the expression of markers specific to mature RPE cells, including MiTF-A, RPE65 or Bestrophin). In accordance with one particular embodiment, the cells are a priori cultured with nicotinamide (NA) which was found to augment the cells' response to the inductive effect of the one or more member of the TGFβ superfamily. The invention also provides methods of performing the directed differentiation, as well as methods for use of the resulting RPE cells.

Members of the TGF-β superfamily and peptide fragments based on member proteins are employed to purify solutions containing member proteins or as therapeutics.

The present invention is directed to methods and compositions for accomplishing systemic delivery of minimally-soluble bioactive agents such as, but not limited to, proteins of the TGF-β superfamily via a peripheral mode of administration. According to the invention, an exemplary bioactive agent is BMP-7. The invention further provides for minimally-invasive systemic treatment of skeletal disorders such as osteoporosis as well as minimally-invasive systemic treatment of injured or diseased non-mineralized tissues and organs such kidneys. Practice of the invention eliminates adverse side effects at the peripheral site of intravenous administration of the bioactive agent.

The present invention provides methods for the treatment, and pharmaceuticals for use in the treatment, of mammalian subjects in, or at risk of chronic renal failure, or at risk of a need for renal replacement therapy. The methods involve the administration of certain proteins of, or based upon, the osteogenic protein / bone morphogenetic protein (OP / BMP) family within the TGF-β superfamily of proteins.

The invention provides modified proteins and DNAs of the TGF-β superfamily including modified morphogenic proteins. The proteins of the present invention display altered biological or biochemical attributes. Specifically, the modified proteins are designed through manipulation or exchange of subdomains among two or more members of the superfamily such that certain desired attributes are mixed-and-matched and then exploited therapeutically.

This invention provides for a protein of the TGF-β superfamily in which the cysteine involved in the normal formation of homodimers is changed to another amino acid. These mutant proteins, as monomers, display higher bone morphogenetic activity than the wild-type protein dimers. Also provided is a method for producing and isolating these monomers by plasmid driven expression in various host systems including E. coli. In addition, the invention discloses the use of an agent containing purified monomers in preventing and treating diseases and problems affecting bone and / or cartilage.

A method of generating retinal pigment epithelial (RPE) cells is disclosed. The method comprises: (a) culturing human pluripotent stem cells in a human feeder cell-conditioned medium to obtain a cultured population of human pluripotent stem cells; (b) culturing said cultured population of human pluripotent stem cells in a medium comprising a differentiating agent to obtain differentiating cells; and (c) culturing said differentiating cells in a medium comprising one or more members of the TGFβ superfamily.

This invention provides for a protein of the TGF-β superfamily in which the cysteine involved in the normal formation of homodimers is changed to another amino acid. These mutant proteins, as monomers, display higher bone morphogenetic activity than the wild-type protein dimers. Also provided is a method for producing and isolating these monomers by plasmid driven expression in various host systems including E. coli. In addition, the invention discloses the use of an agent containing purified monomers in preventing and treating diseases and problems affecting bone and / or cartilage.

The present invention is directed to methods and compositions for systemic delivery of minimally-soluble bioactive agents such as, but not limited to, proteins of the TGF-β superfamily. According to the invention, an exemplary bioactive agent is BMP-7 The invention further provides for minimally-invasive systemic treatment of skeletal disorders such as osteoporosis as well as minimally-invasive systemic treatment of injured or diseased non-mineralized tissues and organs such kidneys. Practice of the invention eliminates adverse side effects at the site of intravascular delivery of the bioactive agent.

In certain aspects, the present disclosure provides compositions and methods for inhibiting activity of TGFβ superfamily ligands, particularly ligands such as GDF8, GDF11, activin A, activin B, activin C and activin E, in vertebrates, including rodents and primates, and particularly in humans. In some embodiments, the compositions of the disclosure may be used to treat or prevent diseases or disorders that are associated with abnormal activity of a follistatin-related polypeptide and / or a follistatin ligand.

Fish sexual characteristics are determined by measuring the concentration in fish serum, plasma or whole blood of one or more peptide hormones of the transforming growth factor-beta superfamily (TGF-β superfamily). The disclosed method and an accompanying field test kit may be used in sturgeon aquaculture to cull out young male fish so that increased time and resources may be devoted to the further rearing of female fish for caviar production. The method and test kit may also be used for wild fish life history studies.

Bioactive molecules are entrapped within a matrix for the controlled delivery of these compounds for therapeutic healing applications. The matrix may be formed of natural or synthetic compounds. The primary method of entrapment of the bioactive molecule is through precipitation of the bioactive molecule during gelation of the matrix, either in vitro or in vivo. The bioactive molecule may be modified to reduce its effective solubility in the matrix to retain it more effectively within the matrix, such as through the deglycosylation of members within the cystine knot growth factor superfamily and particularly within the TGFβ superfamily. The matrix may be modified to include sites with binding affinity for different bioactive molecules, for example, for heparin binding.