Adenovirus-mediated therapy for uterine fibroids

• US 20030199472A1
• Filed: 03/19/2003
• Published: 10/23/2003
• Est. Priority Date: 03/19/2002
• Status: Abandoned Application

• Current Assignee: Northwestern University, Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Northwestern University, Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Jameson, J. Larry, Lee, Eun Jig, Al-Hendy, Ayman
• Application Number:
  US10/392,274
• Publication Number:
  US 20030199472A1
• Time in Patent Office: Days
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material

Abstract

The present invention provides methods of treating and preventing uterine fibroids that is non-surgical, using a modified estrogen receptor gene delivered via an adenoviral vector. The modified estrogen receptor induced apoptosis in vitro and decreased tumor growth in vivo. The invention provides a major improvement above that of current available procedures for women having uterine fibroids, or in preventing fibroids in women at risk of having fibroids. The present invention further provides a safe means of treating fibroids and preserving fertility in young women, or maintaining pregnancy in pregnant women having fibroids.

Claims

1. A method for treating an estrogen-dependent genitourinary condition in a patient comprising administering to the patient an effective amount of an expression construct comprising a nucleic acid comprising a sequence encoding a modified estrogen receptor, wherein the sequence is under the control of a promoter.

2. The method of claim 1, wherein the genitourinary condition is a condition of the uterus.

3. The method of claim 2, wherein the condition is a leiomyoma, adenomyosis, endometriosis, endometrial hyperplasia, leiomyosarcoma, dysfunctional uterine bleeding, or cancer.

4. The method of claim 3, wherein the condition is a leiomyoma.

5. The method of claim 4, wherein the leiomyoma is a submucous, intramural, or subserous fibroid.

6. The method of claim 1, further comprising identifying a patient in need of the treatment.

7. The method of claim 6, wherein the patient is identified by detecting a leiomyoma in the patient.

8. The method of claim 1, wherein the modified estrogen receptor is a modified estrogen receptor α

9. The method of claim 1, wherein the modified estrogen receptor is a modified estrogen receptor β

.

10. The method of claim 1, wherein the expression construct is a viral vector.

11. The method of claim 10, wherein the viral vector is an adenovirus vector, an adeno-associated virus vector, a herpesvirus vector, a lentivirus vector, a retrovirus vector, or a vaccinia virus vector.

12. The method of claim 11, wherein the viral vector is an adenovirus vector.

13. The method of claim 12, wherein the expression construct is Ad-ER1-536.

14. The method of claim 11, wherein the patient is administered about 10³ to about 10¹⁵ viral particles.

15. The method of claim 1, wherein the construct is administered to the patient intrauterinely, intravaginally, intravenously, directly to the affected area, intraperitoneally, or regionally.

16. The method of claim 15, wherein the construct is administered intrauterinely to the patient via a catheter.

17. The method of claim 15, wherein the construct is administered directly to the affected area by injection.

18. The method of claim 1, wherein the construct is administered to the patient more than one time.

19. The method of claim 1, wherein the modified estrogen receptor has a mutation that affects DNA binding activity, transcriptional activation activity, dimerization activity, ligand binding activity, growth hormone binding activity, or binding activity to AP-1 or to a component of AP-1.

20. The method of claim 19, wherein the mutation is a point mutation or deletion.

21. The method of claim 20, wherein the mutation is a point mutation.

22. The method of claim 21, wherein the point mutation is a deletion, a substitution, or an insertion mutation.

23. The method of claim 22, wherein the mutation is at amino acid 540, substituting a charged residue for an uncharged residue.

24. The method of claim 22, wherein the mutation inserts a frameshift at codon 554.

25. The method of claim 20, wherein the mutation is a deletion comprising at least 2 residues.

26. The method of claim 25, wherein the modified estrogen receptor is a truncated receptor.

27. The method of claim 26, wherein the truncated receptor lacks at least 20 contiguous amino acids of SEQ ID NO:

2 or SEQ ID NO;

4.

28. The method of claim 27, wherein the truncated receptor is ER1-530 or ER1-536.

29. The method of claim 4, further comprising removing the leiomyona.

30. The method of claim 1, further comprising administering a second dominant negative estrogen receptor to the patient.

31. The method of claim 30, wherein modified estrogen receptors α

and β

are administered to the patient.

32. A method for inhibiting a leiomyoma cell comprising providing to the cell an effective amount of a dominant negative estrogen receptor, wherein the leiomyoma cell is inhibited.

33. The method of claim 32, wherein the dominant negative estrogen receptor is a dominant negative estrogen receptor α

.

34. The method of claim 32, wherein the leiomyoma is a uterine leiomyoma.

35. The method of claim 32, wherein the modified estrogen receptor is provided to the cell by administering to the cell an adenovirus vector comprising a nucleic acid sequence, under the control of a promoter, encoding the modified estrogen receptor, wherein the modified estrogen receptor is expressed in the cell.

36. The method of claim 35, wherein the promoter is a CMV IE promoter.

37. The method of claim 36, wherein the adenovirus vector comprising the nucleic acid sequence, under the control of a promoter, encoding the modified estrogen receptor is Ad-ER1-536.

38. The method of claim 32, wherein the leiomyoma cell undergoes apoptosis.

39. The method of claim 32, wherein the leiomyoma cell is in a patient.

40. The method of claim 32, wherein the modified estrogen receptor has a mutation that affects DNA binding activity, transcriptional activation activity, dimerization activity, ligand binding activity, or growth hormone binding activity, binding activity to AP-1 or to a component of AP-1.

41. The method of claim 40, wherein the mutation is a point mutation or deletion.

42. The method of claim 41, wherein the mutation is a point mutation.

43. The method of claim 42, wherein the point mutation is a deletion, a substitution, or an insertion mutation.

44. The method of claim 43, wherein the mutation is a substitution.

45. The method of claim 44, wherein the mutation is at amino acid 540, substituting a charged residue for an uncharged residue.

46. The method of claim 43, wherein the point mutation inserts a frameshift.

47. The method of claim 41, wherein the mutation is a deletion comprising at least 2 residues.

48. The method of claim 61, wherein the modified estrogen receptor is a truncated receptor.

49. The method of claim 48, wherein the truncated receptor is ER1-530 or ER1-536.

50. The method of claim 48, wherein the truncated receptor lacks at least 20 contiguous amino acids of SEQ ID NO:

2.

51. A method of treating a uterine fibroid in a patient comprising administering to the patient an effective amount of an adenovirus construct comprising a nucleic acid sequence, under the control of a promoter, encoding an estrogen receptor that is capable of binding to a ligand and has a reduced ability to activate transcription of an estrogen-dependent gene, wherein the fibroid is reduced.

52. The method of claim 51, wherein the construct is administered more than once.

53. The method of claim 51, wherein the estrogen receptor has a mutation in a transactivation domain, in a DNA binding domain, or in a region mediating protein-protein interaction.

54. A method of preventing pregnancy in a female subject comprising administering an effective amount of an expression construct comprising a nucleic acid, under the control of a promoter, encoding a modified estrogen receptor, wherein pregnancy is prevented.

55. The method of claim 54, wherein the expression construct is a viral vector.

56. The method of claim 54, wherein the modified estrogen receptor has a mutation that affects DNA binding activity, transcriptional activation activity, dimerization activity, ligand binding activity, or growth hormone binding activity, binding activity to AP-1 or to a component of AP-1.

57. The method of claim 54 wherein the modified estrogen receptor is a dominant-negative estrogen receptor.

58. The method of claim 57, wherein the dominant-negative estrogen receptor is ER1-536.

59. The method of claim 54, further comprising administering to a female subject a second agent for preventing conception.