Method of treating fibrosis in a subject in need thereof comprising administering a composition comprising a CSD
Inventors
Hoffman, Stanley • Tourkina, Elena
Assignees
Medical University of South Carolina MUSC • SanDisk Corp
Publication Number
US-8058227-B2
Publication Date
2011-11-15
Expiration Date
2027-10-03
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Abstract
Disclosed are compositions and methods for the treatment of fibrosis. Also disclosed are methods of screening for agents that treat fibrosis.
Core Innovation
The invention discloses methods and compositions for the treatment of fibrosis by administering a composition comprising a caveolin-1 scaffolding domain (CSD) moiety or a fragment, derivative, or analogue thereof. The treatment utilizes the inhibitory effects of the CSD peptide on key signaling pathways that drive the overexpression of extracellular matrix proteins, especially collagen, by fibrotic cells in tissues affected by diseases such as scleroderma.
The main problem addressed is the lack of effective and safe treatments for fibrosis, particularly in scleroderma lung disease, where fibrosis is characterized by an excessive buildup of extracellular matrix proteins like collagen driven by activated myofibroblasts. Conventional treatments are insufficient to halt or reverse these processes, and there is a need for new therapeutic approaches targeting the signaling mechanisms underlying fibrotic progression.
This invention reveals that administering a CSD moiety, including peptides derived from the CSD sequence, fusion peptides with the Antennapedia internalization sequence, myristoylated versions, or peptoids, can inhibit the activation of signaling molecules such as MEK, ERK, JNK, and Akt. It leads to decreased expression of collagen, tenascin-C, and α-smooth muscle actin (ASMA) in both in vitro human fibroblasts and in vivo mouse models of lung fibrosis. These results support the use of CSD-based compositions as therapeutic agents for treating a wide range of fibrotic disorders.
Claims Coverage
The patent claims cover one main independent inventive feature regarding the treatment of fibrosis using compositions comprising a specific caveolin-1 scaffolding domain (CSD) moiety or specific fragments thereof.
Method of treating fibrosis with a composition comprising a caveolin-1 scaffolding domain (CSD) moiety as set forth in SEQ ID NO: 1 or a fragment thereof comprising the B and C subdomains
This inventive feature covers a therapeutic method for treating fibrosis in a subject by administering a composition that contains a caveolin-1 scaffolding domain (CSD) moiety as set forth in SEQ ID NO: 1, or a fragment comprising the B and C subdomains of CSD. The coverage explicitly includes: - The CSD moiety being a peptide. - The peptide formulated as a fusion peptide with the C-terminus of an Antennapedia internalization sequence (SEQ ID NO: 3). - The peptide being myristoylated or modified to be a peptoid. - The CSD moiety being a peptidomimetic. - The option to administer the composition in combination with curcumin. - The method's application to various forms of fibrosis, including but not limited to pulmonary fibrosis from scleroderma, idiopathic pulmonary fibrosis (IPF), various pneumonias, drug/radiation-induced fibrosis, rheumatologic diseases, and fibrosis resulting from myocardial infarction, injury, surgery, or therapeutic radiation.
The claims define the therapeutic use of specific CSD-containing compositions, including various peptide, peptoid, and fusion formats, for the treatment of a broad array of fibrotic diseases and conditions in human subjects.
Stated Advantages
The compositions and methods can inhibit collagen, tenascin-C, and ASMA expression both in vitro and in vivo, blocking key molecular pathways underlying fibrotic tissue changes.
Systemic administration of CSD peptide effectively blocks changes in tissue morphology, signaling molecule activation, and extracellular matrix protein expression associated with fibrosis.
The method provides notable protection against progression of fibrosis, as shown by improved survival and reduced tissue damage in animal models.
Variants of the CSD peptide such as subdomains, myristoylated forms, and peptoids offer potential for improved solubility, specificity, resistance to proteolysis, and cellular uptake.
Documented Applications
Treatment of pulmonary fibrosis caused by scleroderma lung disease, idiopathic pulmonary fibrosis (IPF), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), Acute Respiratory Distress Syndrome (ARDS), asbestosis, accidental or therapeutic radiation induced lung fibrosis, Rheumatoid Arthritis, Sarcoidosis, Silicosis, Tuberculosis, Hermansky Pudlak Syndrome, Bagassosis, Systemic Lupus Erythematosis, Eosinophilic granuloma, Wegener's granulomatosis, Lymphangioleiomyomatosis, Cystic Fibrosis, and fibrosis from drug exposures including Nitrofurantoin, Amiodarone, Bleomycin, cyclophosphamide, or methotrexate.
Treatment of fibrosis resulting from myocardial infarction, injury related tissue scarring, surgical scarring, and therapeutic radiation induced fibrosis, including fibrosis in the throat following radiation for throat cancer.
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