COMPOSITIONS AND METHODS FOR THE TREATMENT OF DISEASE
The present invention relates to pharmaceutical compositions for the treatment and/or prophylaxis of disease associated with fibrosis in a vertebrate, said composition comprising at least one activin antagonist, and optionally a pharmaceutically acceptable carrier, adjuvant and/or diluent. The invention also relates to methods of treatment of disease associated with fibrosis in a vertebrate, as well as methods for diagnosing such conditions, and kits therefor.
1 . A method for the treatment of disease associated with fibrosis in a vertebrate in need of said treatment, wherein said method comprises administering to said vertebrate a therapeutically effective amount of a composition comprising at least one activin antagonist.
2 . The method of claim 1 , wherein said composition comprising at least one activin antagonist further comprises a pharmaceutically acceptable carrier, adjuvant or diluent.
3 . The method of claim 1 , wherein the activin antagonist is follistatin or a fragment(s) or analogue thereof.
4 . The method of claim 3 , wherein the follistatin is a single chain protein comprising between 288 and 315 amino acids with a molecular weight of between about 30,000 and 60,000 Daltons as estimated by SDS-PAGE in the absence of reducing agents, derived from follicular fluid and able to inhibit the secretion of follicle-stimulating hormone (FSH).
5 . The method of claim 3 , wherein the follistatin is a single chain protein classified as NCBI (National Center for Biotechnology Information) protein XP — 003891, AAH04107.
6 . The method of claim 3 , wherein the follistatin or a fragment(s) or analogue present in the pharmaceutical composition exists in a form selected from the group consisting of: follistatin/chelate, follistatin/drug, follistatin/prodrug, follistatin/toxin and follistatin/detector group and follistatin/imaging marker.
7 . The method of claim 1 , wherein the activin antagonist is follistatin-related protein or a fragment(s) or analogue thereof.
8 . The method of claim 7 , wherein the follistatin-related protein has a sequence as defined in Genbank accession number NP — 005851.
9 . The method of claim 1 , wherein the activin antagonist is an antibody raised against activin.
10 . The method of claim 9 , wherein the activin to which the antibody is raised is activin A, activin AB or activin B.
11 . The method of claim 9 , wherein the activin to which the antibody is raised is a heterodimer or homodimer of mature inhibin βA or βB subunit chains free of inhibin a chain.
12 . The method of claim 11 , wherein the two subunits comprise between 110 and 120 amino acids with molecular weights of about 12,000-13,000 Daltons as estimated by SDS-PAGE in the absence of reducing agents.
13 . The method of claim 11 , wherein the activin contains PA subunit with sequence as defined in GenBank accession number M13436 and/or SB subunit with sequence defined in GenBank accession number M13437.
14 . The method of claim 1 , wherein the activin antagonist is a compound which interferes with activin binding to its respective receptor.
15 . The method of claim 14 , wherein said compound is an antibody raised against the activin receptor.
16 . The method of claim 15 , wherein the activin receptor to which the antibody is raised is ActRIIA or ActRIIB or ActRIA or ActRIB or ALK2 or ALK4.
17 . The method of claim 14 , wherein the compound is an antibody raised against receptor for a protein selected from the group consisting of: activin A, activin AB and activin B.
18 . The method of claim 14 , wherein said compound is a Smad signalling molecule selected from Smad6 and Smad7 or fragment(s) or analogue(s) thereof.
19 . The method of claim 14 , wherein said compound is a molecule that specifically inhibits TGFβ/activin type I receptors.
20 . The method of claim 19 , wherein said compound is selected from triarylimidazole analogues.
21 . The method of claim 20 , wherein said compound is SB-431542.
22 . The method of claim 1 , wherein the vertebrate is selected from the group consisting of human, non-human primate, mice, cattle, sheep, goats, horses, rabbits, birds, cats and dogs.
23 . The method of claim 22 , wherein the vertebrate is human.
24 . The method of claim 1 , wherein the disease associated with fibrosis is one of: a hyperproliferative or inflammatory fibrotic disease; a pulmonary fibrosis; an inflammatory bowel disease, or a related condition such as ulcerative colitis or Crohn's Disease; or liver fibrosis or cirrhosis.
25 . The method of claim 24 , wherein the disease associated with fibrosis is liver fibrosis or cirrhosis.
26 . A method of gene therapy for the treatment of disease associated with fibrosis in a vertebrate, wherein said method comprises:
(a) inserting a nucleic acid molecule encoding for an activin antagonist, or fragment(s) or analogue thereof, or a vector comprising a nucleic acid molecule encoding for an activin antagonist or a fragment(s) or analogue thereof, into a host cell;
(b) expressing the nucleic acid molecule in the transformed cell.