Regulation of lung tissue by hedgehog-like polypeptides and formulations and uses related thereto

• US 20040171546A1
• Filed: 12/03/2003
• Published: 09/02/2004
• Est. Priority Date: 09/11/1998
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: McMahon, Andrew P., Pepicelli, Carmen V., Lewis, Paula M.
• Granted Patent: US 7,691,593 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/46 from vertebrates
• CPC Class Codes: C12N 5/0688 Cells from the lungs or the respiratory tract

Abstract

The present application relates to a method for modulating the growth state of an lung tissue, or a cell thereof, e.g., by ectopically contacting the tissue, in vitro or in vivo, with a hedgehog therapeutic, a ptc therapeutic, or an FGF-10 therapeutic in an amount effective to alter the rate (promote or inhibit) of proliferation of cells in the lung tissue, e.g., relative to the absence of administeration of the hedgehog therapeutic or ptc therapeutic. The subject method can be used, for example, to modulate the growth state of epithelial and/or mesenchymal cells of a lung tissue, such as may be useful as part of a regimen for prevention of a disease state, or in the treatment of an existing disease state or other damage to the lung tissue.

Claims

1. A method for modulating the growth state of lung tissue, or cells derived therefrom, comprising ectopically contacting the tissue with an amount of an agent effective to alter the rate of proliferation of the lung tissue, wherein the agent is selected from the group consisting of a hedgehog therapeutic, a ptc therapeutic and an fgf-10 therapeutic.

3. The method of claim 1, wherein the lung tissue is in culture, and the agent is provided as a cell culture additive.

4. The method of claim 1, wherein the cell is treated in an animal and the agent is administered to the animal as a therapeutic composition.

5. The method of claim 1, wherein the agent is a hedgehog therapeutic.

6. The method of claim 5, wherein the hedgehog therapeutic is a polypeptide including a hedgehog polypeptide sequence of at least a bioactive extracellular portion of a hedgehog protein.

7. The method of claim 6, wherein the polypeptide includes at least 50 amino acids residues of an N-terminal half of the hedgehog protein

8. The method of claim 6, wherein the polypeptide includes at least 100 amino acids of an extracellular domain of the hedgehog protein.

9. The method of claim 6, wherein the polypeptide includes at least a portion of the hedgehog protein corresponding to a 19 kd fragment of an extracellular domain of the hedgehog protein.

10. The method of claim 6, wherein the hedgehog protein is encoded by a gene of a vertebrate organism.

11. The method of claim 6, wherein the polypeptide includes a hedgehog polypeptide sequence represented in the general formula of SEQ ID No. 21.

12. The method of claim 6, wherein the polypeptide includes a hedgehog polypeptide sequence represented in the general formula of SEQ ID No. 22.

13. The method of claim 6, wherein the hedgehog protein is encoded by a human hedgehog gene.

14. The method of claim 6, wherein the hedgehog polypeptide sequence is at least 60 percent identical to an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:

9, SEQ ID No;

10, SEQ ID No;

11, SEQ ID No;

12, SEQ ID No;

13, SEQ ID No;

14, SEQ ID No;

15 and SEQ ID No;

16.

15. The method of claim 6, wherein the hedgehog polypeptide sequence is encodable by a nucleotide sequence which hybridizes under stringent conditions to a sequence selected from the group consisting of SEQ ID No:

1, SEQ ID No;

2, SEQ ID No;

3, SEQ ID No;

4, SEQ ID No;

5, SEQ ID No;

6, SEQ ID No;

7 and SEQ ID No;

8.

16. The method of claim 6, wherein the hedgehog polypeptide sequence is an amino acid sequence of a hedgehog protein selected from the group consisting of SEQ ID No:

9, SEQ ID No;

10, SEQ ID No;

11, SEQ ID No;

12, SEQ ID No;

13, SEQ ID No;

14, SEQ ID No;

15 and SEQ ID No;

16.

17. The method of claim 6, wherein the hedgehog polypeptide sequence is an amino acid sequence of a Sonic hedgehog protein.

18. The method of claim 1, wherein the agent is a ptc therapeutic.

19. The method of claim 18, wherein the ptc therapeutic is a small organic molecule which binds to a patched protein and derepresses patched-mediated inhibition of mitosis.

20. The method of claims 18, wherein the ptc therapeutic binds to patched and mimics hedgehog-mediated patched signal transduction.

21. The method of claim 20, wherein the ptc therapeutic is a small organic molecule.

2. A method for inducing the formation of, or the maintenance or functiona performance of lung tissue, comprising contacting the lung tissue with an amount of an agent effective to induce the formation of new lung tissue, wherein the agent is selected from the group consisting of a hedgehog therapeutic, a ptc therapeutic and an fgf-10 therapeutic.