MITIGATING TISSUE DAMAGE AND FIBROSIS VIA LATENT TRANSFORMING GROWTH FACTOR BETA BINDING PROTEIN (LTBP4)
The disclosure relates to compositions and methods of mitigating tissue damage and fibrosis in a patient by modulating latent transforming growth factor beta binding protein (LTBP4)-induced proteolysis of a TGFβ superfamily protein.
1 . A method of treating a patient having a transforming growth factor beta (TGFβ) superfamily protein-related disease, comprising administering a therapeutically effective amount of an agent that modulates proteolysis of latent TGFβ binding protein 4 (LTBP4) to a patient in need thereof.
2 . A method of delaying onset or preventing a transforming growth factor beta (TGFβ) superfamily protein-related disease, comprising administering an effective amount of an agent that modulates proteolysis of latent TGFβ binding protein 4 (LTBP4) to a patient in need thereof.
3 . The method of claim 1 or claim 2 wherein the patient suffers from a disease selected from the group consisting of Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury and colon cancer.
4 . The method of any one of claims 1 - 3 wherein the agent is selected from the group consisting of an anti-LTBP4 antibody and a peptide.
5 . The method of any one of claims 1 - 4 further comprising administering an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent, and a modulator of fibrosis.
6 . A method of treating a patient having a transforming growth factor beta (TGFβ) superfamily protein-related disease, comprising administering to the patient a therapeutically effective amount of an agent that upregulates the activity of latent TGFβ binding protein 4 (LTBP4).
7 . A method of delaying onset or preventing a transforming growth factor beta (TGFβ) superfamily protein-related disease, comprising administering to the patient an effective amount of an agent that upregulates the activity of latent TGFβ binding protein 4 (LTBP4).
8 . The method of claim 6 or claim 7 wherein LTBP4 interacts with a TGFβ superfamily protein.
9 . The method of any one of claim 8 wherein the TGFβ superfamily protein is selected from the group consisting of TGFβ, a growth and differentiation factor (GDF), activin, inhibin, and a bone morphogenetic protein.
10 . The method of claim 9 wherein the GDF is myostatin.
11 . The method of any one of claims 6 - 10 wherein the agent is selected from the group consisting of a peptide, an antibody and a polynucleotide capable of expressing a protein having LTBP4 activity.
12 . The method of claim 11 wherein the agent is the peptide of claim 21 .
13 . The method of claim 11 wherein the agent is the antibody of claim 20 .
14 . The method of claim 11 wherein the polynucleotide is contained in a vector.
15 . The method of claim 14 wherein the vector is a viral vector.
16 . The method of claim 15 wherein the viral vector is selected from the group consisting of a herpes virus vector, an adeno-associated virus (AAV) vector, an adeno virus vector, and a lentiviral vector.
17 . The method of claim 16 wherein the AAV vector is recombinant AAV9.
18 . The method of any one of claims 6 - 17 wherein the patient has a disease selected from the group consisting of Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Becker Muscular Dystrophy, myopathy, cystic fibrosis, pulmonary fibrosis, cardiomyopathy, acute lung injury, acute muscle injury, acute myocardial injury, radiation-induced injury, and colon cancer.
19 . The method of any one of claims 6 - 18 further comprising administering an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.
20 . An isolated antibody that specifically binds to a peptide comprising the sequence set forth in SEQ ID NO: 5.
21 . A peptide comprising the sequence as set out in any one of SEQ ID NOs: 2-5, or a peptide that is at least 70% identical to the sequence as set out in SEQ ID NOs: 2-5 that retains an ability to act as a substrate for a protease.
22 . A pharmaceutical formulation comprising an effective amount of the antibody of claim 20 or the peptide of claim 21 , and a pharmaceutically acceptable carrier or diluent.
23 . A kit comprising a therapeutically effective amount of the antibody of claim 20 or the peptide of claim 21 , a pharmaceutically acceptable carrier or diluent and instructions for use.
24 . The formulation of claim 22 or the kit of claim 23 , further comprising an effective amount of a second agent, wherein the second agent is selected from the group consisting of a modulator of an inflammatory response, a promoter of muscle growth, a chemotherapeutic agent and a modulator of fibrosis.