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

• US 6,639,051 B2
• Filed: 09/11/1998
• Issued: 10/28/2003
• Est. Priority Date: 10/20/1997
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Wang, Elizabeth A.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Lukton, David
• Application Number:
  US09/151,999
• Publication Number:
  US 20020151460A1
• Time in Patent Office: 1,873 Days
• Field of Search: 514/2, 514/121, 514/21, 530/300, 530/324, 530/350, 424/185.1, 424/198.1, 435/69.1
• US Class Current: 530/350
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 8/606 Nucleosides; Nucleotides; Nucleic acids
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations
• CPC Class Codes: A61Q 7/00 Preparations for affecting hair growth
• CPC Class Codes: A61Q 7/02 Preparations for inhibiting or slowing hair growth
• CPC Class Codes: C07K 14/43581 from Drosophila
• CPC Class Codes: C07K 14/461 from fish
• CPC Class Codes: C07K 14/465 from birds
• CPC Class Codes: C07K 14/4702 : Regulators; Modulating activity
• CPC Class Codes: C12N 2501/41 : Hedgehog proteins; Cyclopamine (inhibitor)
• CPC Class Codes: C12N 2501/70 : Enzymes
• CPC Class Codes: C12N 5/0627 : Hair cells
• CPC Class Codes: C12N 5/0629 : Keratinocytes; Whole skin

Abstract

The invention provides methods and compositions for modulating hair growth.

Claims

1. A method for promoting growth of hair on skin of a mammal, comprising administering an agent to the mammal for a time and under conditions effective to promote growth of hair on the skin of the mammal, wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and wherein said hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from

(i) binding to patched;

(ii) altering the binding or enzymatic activity of a protein involved in hedgehog signal transduction;

or

(iii) altering expression of a hedgehog protein, a patched protein or a protein involved in hedgehog signal transduction.

2. The method of claim 1, wherein the agent is a patched antagonist.

3. The method of claim 2, wherein the patched antagonist binds to patched and mimics hedgehog-mediated patched signal transduction.

4. The method of claim 3, wherein the binding of the patched antagonist to patched results in upregulation of patched and/or glioma-associated oncogene homolog (gli) expression.

5. The method of claim 2, wherein the patched antagonist alters the level of expression of a hedgehog protein, a patched protein or a protein involved in the intracellular signal transduction pathway of patched.

6. The method of claim 1, wherein the agent is a hedgehog agonist.

7. The method of claim 6, wherein the hedgehog agonist is a peptidomimetic of a hedgehog polypeptide sequence.

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

9. The method of claim 8, wherein the polypeptide includes at least 50 contiguous amino acids residues of an N-terminal half of the hedgehog protein.

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

11. The method of claim 8, wherein the polypeptide includes at least a 19 kd fragment of an extracellular domain of the hedgehog protein.

12. The method of claim 8, wherein the hedgehog protein is encoded by a gene of a vertebrate organism.

13. The method of claim 8, wherein the polypeptide includes a hedgehog polypeptide sequence represented in SEQ ID No:

21.

14. The method of claim 13, 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.

15. The method of claim 8, wherein the polypeptide includes a hedgehog polypeptide sequence represented in SEQ ID No:

22.

16. The method of claim 8, wherein the hedgehog protein is encoded by a human hedgehog gene.

17. The method of claim 8, 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.

18. The method of claim 17, wherein the hedgehog polypeptide sequence is at least 75 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.

19. The method of claim 17, wherein the hedgehog polypeptide sequence is at least 85 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.

20. The method of claim 8, wherein the hedgehog polypeptide sequence is an amino acid sequence of a Sonic hedgehog protein.

21. The method of claim 8, wherein the hedgehog polypeptide sequence is an amino acid sequence of a Desert hedgehog protein.

22. The method of claim 8, wherein the hedgehog polypeptide sequence is an amino acid sequence of an Indian hedgehog protein.

23. The method of claim 8, wherein the hedgehog polypeptide sequence includes amino acid residues 24-193 of SEQ ID No:

15.

24. The method of claim 8, wherein the polypeptide is purified to at least 80% by dry weight.

25. The method of claim 8, wherein the polypeptide is a recombinantly produced polypeptide.

26. The method of claim 8, wherein the polypeptide is a chemically synthesized polypeptide.

27. A method for promoting growth of hair on skin of a mammal, comprising administering a composition to the mammal for a time and under conditions effective to promote growth of hair on the skin of the mammal, wherein said composition comprises an agent and an acceptable carrier or excipient, and wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and further said hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from

(i) binding to patched;

(ii) altering the binding or enzymatic activity of a protein involved in hedgehog signal transduction;

or

(iii) altering expression of a hedgehog protein, a patched protein or a protein involved in hedgehog signal transduction.

28. The method of claim 27, wherein the composition is applied topically.