Inhibition of pulmonary fibrosis with nutlin-3A and peptides

Patent metadata

Field	Value
Publication number	US-9630990-B2
Application number	US-201414775895-A
Country	US
Kind code	B2
Filing date	Mar 17, 2014
Priority date	Mar 15, 2013
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

Abstract

In fibrotic lung fibroblasts, basal levels of p53 protein (and miR-34a) are markedly suppressed, leading to reduced p53-mediated inhibition of uPA and uPAR, or concurrent induction of PAI-1. These changes contribute to excessive FL-fibroblast proliferation and production of extracellular matrix (ECM), and, therefore, pulmonary fibrosis. These processes are reversed by treating the cells, and treating subjects suffering from idiopathic pulmonary fibrosis (IPF) with the small organic molecule nutlin-3a (NTL) or with a peptide, CSP-4 (SEQ ID NO:1), or variants or derivatives or multimers of this peptide, which increase p53 levels by inhibiting MDM2-mediated degradation of p53 protein. Use of these compounds serves as a new approach to the treatment of IPF, they restore p53 expression and p53-mediated changes in the uPA-fibrinolytic system in FL-fibroblasts and restrict production and deposition of ECM.

First claim

What is claimed is:

1. A method of treating a subject having a disease or condition characterized by fibrosis, comprising administering an effective amount of a pharmaceutical composition comprising a recombinant polypeptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO:1) and, optionally, including 1-5 amino acids of additional sequence at the N- and/or C-terminus of the sequence of SEQ ID NO: 1 to the subject.

2. The method of claim 1 , wherein the fibrosis is pulmonary fibrosis.

3. The method of claim 2 , wherein the fibrosis is idiopathic pulmonary fibrosis.

4. The method of claim 1 , wherein the subject is human.

5. The method of claim 1 , wherein the pharmaceutical composition is administered systemically.

6. The method of claim 4 , wherein the pharmaceutical composition is administered intranasally, intrabronchially, intrapleurally or by instillation into lungs of the subject.

7. The method of claim 1 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 1).

8. The method of claim 1 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 1) and 1-5 amino acids of additional sequence at the N-terminus.

9. The method of claim 1 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 1) and 1-5 amino acids of additional sequence at the C-terminus.

10. The method of claim 1 , wherein the polypeptide comprises L-amino acids.

11. The method of claim 1 , wherein the polypeptide comprises at least one D-amino acid.

12. The method of claim 1 , wherein the polypeptide is capped at its N and/or C termini.

13. The method of claim 1 , wherein the composition is formulated for injection or lung instillation.

14. The method of claim 13 , wherein the composition is formulated for lung instillation.

15. The method of claim 1 , wherein the composition is formulated for oral, parenteral, topical, transdermal, intravaginal, intrapenile, intranasal, intrabronchial, intracranial, intraocular, intraaural or rectal administration.

Assignees

• Univ Texas

Inventors

• Shetty Sreerama
• Idell Steven

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/497 Primary

  containing further heterocyclic rings · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title