Enhancing neurotrophin-induced neurogenesis by endogenous neural progenitor cells by concurrent overexpression of brain derived neurotrophic factor and an inhibitor of a pro-gliogenic bone morphogenetic protein

• US 20030199447A1
• Filed: 02/14/2003
• Published: 10/23/2003
• Est. Priority Date: 02/15/2002
• Status: Active Grant

• Current Assignee: Cornell Research Foundation Incorporated (Cornell University), Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Goldman, Steven A., Economides, Aris, Chmielnicki, Eva
• Granted Patent: US 7,576,065 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• 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: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2840/203 having an IRES

Abstract

The present invention relates to a method of inducing neuronal production in a subject, a method of recruiting neurons to a subject'"'"'s brain, and a method of treating a neurodegenerative condition by administering a neurotrophic factor and an inhibitor of pro-gliogenic bone morphogenetic proteins. Also disclosed is a method of suppressing astrocyte generation and inducing neuronal production in a subject, a method of treating a neurologic condition, and a method of suppressing glial scar formation in a subject by administering an inhibitor of pro-gliogenic bone morphogenetic proteins. Finally, the present invention involves a method of introducing a heterogeneous protein into a subject'"'"'s brain and spinal cord by introducing a nucleic acid molecule encoding the heterogeneous protein introduced into the subject'"'"'s ependyma, permitting the protein from the nucleic acid molecule to be expressed within the subject'"'"'s ependyma, and permitting the expressed protein to migrate within the subject'"'"'s brain and spinal cord.

Claims

1. A method of inducing neuronal production in a subject comprising:

providing a neurotrophic factor;

providing an inhibitor of pro-gliogenic bone morphogenetic proteins; and

administering the neurotrophic factor and the inhibitor into the subject'"'"'s lateral ventricles or ventricular wall under conditions effective to induce neuronal production in the brain and spinal cord of the subject.

2. The method according to claim 1, wherein the neurotrophic factor is administered as a protein or polypeptide.

3. The method according to claim 1, wherein the inhibitor is administered as a protein or polypeptide.

4. The method according to claim 1, wherein the neurotrophic factor is administered as a nucleic acid construct encoding the neurotrophic factor.

5. The method according to claim 4, wherein the nucleic acid construct is in a viral vector.

6. The method according to claim 5, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

7. The method according to claim 4, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the neurotrophic factor.

8. The method according to claim 4, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the neurotrophic factor.

9. The method according to claim 4, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the neurotrophic factor.

10. The method according to claim 1, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

11. The method according to claim 10, wherein the nucleic acid construct is in a viral vector.

12. The method according to claim 11, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

13. The method according to claim 10, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the inhibitor.

14. The method according to claim 10, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the inhibitor.

15. The method according to claim 10, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

16. The method according to claim 1, wherein the neurotrophic factor is brain-derived neurotrophic factor.

17. The method according to claim 1, wherein the neurotrophic factor is neurotrophin-4/5.

18. The method according to claim 1, wherein the neurotrophic factor is neurotrophin-3.

19. The method according to claim 1, wherein the neurotrophic factor is insulin-like growth factor-1.

20. The method according to claim 1, wherein the inhibitor is noggin with its heparin binding site removed.

21. A method of recruiting neurons to a subject'"'"'s brain comprising:

providing a neurotrophic factor;

providing an inhibitor of pro-gliogenic bone morphogenetic proteins; and

administering the neurotrophic factor and the inhibitor into the subject'"'"'s lateral ventricles or ventricular wall under conditions effective to recruit neurons to the brain of the subject.

22. The method according to claim 21, wherein the neurotrophic factor is administered as a protein or polypeptide.

23. The method according to claim 21, wherein the inhibitor is administered as a protein or polypeptide.

24. The method according to claim 21, wherein the neurotrophic factor is administered as a nucleic acid construct encoding the neurotrophic factor.

25. The method according to claim 24, wherein the nucleic acid construct is in a viral vector.

26. The method according to claim 25, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

27. The method according to claim 24, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the neurotrophic factor.

28. The method according to claim 24, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the neurotrophic factor.

29. The method according to claim 24, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the neurotrophic factor.

30. The method according to claim 21, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

31. The method according to claim 30, wherein the nucleic acid construct is in a viral vector.

32. The method according to claim 31, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

33. The method according to claim 30, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the inhibitor.

34. The method according to claim 30, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

35. The method according to claim 30, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the inhibitor.

36. The method according to claim 21, wherein the neurotrophic factor is brain-derived neurotrophic factor.

37. The method according to claim 21, wherein the neurotrophic factor is neurotrophin-4/5.

38. The method according to claim 21, wherein the neurotrophic factor is neurotrophin-3.

39. The method according to claim 21, wherein the neurotrophic factor is insulin-like growth factor-1.

40. The method according to claim 21, wherein the inhibitor is noggin with its heparin binding site removed.

41. The method according to claim 21, wherein recruitment of neurons is to the olfactory bulb.

42. The method according to claim 21, wherein recruitment is to the basal ganglia of the brain, the caudate nucleus, the putamen, and/or the globus pallidus.

43. The method according to claim 21, wherein recruitment of neurons is to the cortex.

44. A method of treating a neurodegenerative condition comprising:

providing a neurotrophic factor;

providing an inhibitor of pro-gliogenic bone morphogenetic proteins; and

administering the neurotrophic factor and the inhibitor into the subject'"'"'s lateral ventricles or ventricular zone wall under conditions effective to treat a neurodegenerative condition.

45. The method according to claim 44, wherein the neurodegenerative condition is selected from the group consisting of Huntington'"'"'s Disease, Parkinson'"'"'s Disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and traumatic injury to the brain and spinal cord.

46. The method according to claim 45, wherein the neurodegenerative condition is Huntington'"'"'s Disease.

47. The method according to claim 45, wherein the neurodegenerative condition is traumatic brain injury.

48. The method according to claim 45, wherein the neurodegenerative condition is stroke.

49. The method according to claim 44, wherein the neurotrophic factor is administered as a protein or polypeptide.

50. The method according to claim 44, wherein the inhibitor is administered as a protein or polypeptide.

51. The method according to claim 44, wherein the neurotrophic factor is administered as a nucleic acid construct encoding the neurotrophic factor.

52. The method according to claim 51, wherein the nucleic acid construct is in a viral vector.

53. The method according to claim 52, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof

54. The method according to claim 51 wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the neurotrophic factor.

55. The method according to claim 51, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the neurotrophic factor.

56. The method according to claim 51, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the neurotrophic factor.

57. The method according to claim 44, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

58. The method according to claim 57, wherein the nucleic acid construct is in a viral vector.

59. The method according to claim 58, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

60. The method according to claim 57, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the inhibitor.

61. The method according to claim 57, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

62. The method according to claim 57, wherein the nucleic acid construct farther comprises an inducible or conditional promotor for controlling expression of the inhibitor.

63. The method according to claim 44, wherein the neurotrophic factor is brain-derived neurotrophic factor.

64. The method according to claim 44, wherein the neurotrophic factor is neurotrophin-4/5.

65. The method according to claim 44, wherein the neurotrophic factor is neurotrophin-3.

66. The method according to claim 44, wherein the neurotrophic factor is insulin-like growth factor-1.

67. The method according to claim 44, wherein the inhibitor is noggin with its heparin binding site removed.

68. A method of suppressing astrocyte generation and inducing neuronal production in a subject comprising:

providing an inhibitor of pro-gliogenic bone morphogenetic proteins and

administering the inhibitor into the subject'"'"'s lateral ventricles or ventricular wall under conditions effective to suppress astrocyte generation and induce neuronal production in the brain and spinal cord of the subject.

69. The method according to claim 68, wherein the inhibitor is administered as a protein or polypeptide.

70. The method according to claim 68, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

71. The method according to claim 70, wherein the nucleic acid construct is in a viral vector.

72. The method according to claim 71, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

73. The method according to claim 70, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the inhibitor.

74. The method according to claim 70, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

75. The method according to claim 70, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the inhibitor.

76. The method according to claim 68, wherein the inhibitor is noggin with its heparin binding site removed.

77. A method of treating a neurologic condition in a subject comprising:

providing an inhibitor of pro-gliogenic bone morphogenetic proteins and

administering the inhibitor to the subject'"'"'s lateral ventricles, ventricular wall, or site of injury under conditions effective to treat a neurodegenerative condition.

78. The method according to claim 77, wherein the neurologic condition is selected from the group consisting of Huntington'"'"'s Disease, Parkinson'"'"'s Disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, a condition mediated or exacerbated by glial scar formation, and traumatic injury to the brain and spinal cord.

79. The method according to claim 78, wherein the neurologic condition is Huntington'"'"'s Disease.

80. The method according to claim 78, wherein the neurologic condition is or results from traumatic brain injury.

81. The method according to claim 78, wherein the neurologic condition is or results from traumatic spinal cord injury.

82. The method according to claim 78, wherein the neurologic condition is stroke.

83. The method according to claim 78, wherein the neurologic condition is a condition mediated or exacerbated by glial scar formation.

84. The method according to claim 77, wherein the inhibitor is administered as a protein or polypeptide.

85. The method according to claim 77, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

86. The method according to claim 85, wherein the nucleic acid construct is in a viral vector.

87. The method according to claim 86, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

88. The method according to claim 85, wherein the nucleic acid construct further comprises a constitutive promoter for controlling expression of the inhibitor.

89. The method according to claim 85, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

90. The method according to claim 85, wherein the nucleic acid construct further comprises an inducible or conditional promotor for controlling expression of the inhibitor.

91. The method according to claim 77, wherein the inhibitor is noggin with its heparin binding site removed.

92. A method of suppressing glial scar formation in a subject comprising:

providing an inhibitor of progliogenic bone morphogenic proteins and

administering the inhibitor of progliogenic bone morphogenic proteins to the subject'"'"'s ventricles, ventricular wall, or sites of injury at risk for glial scar formation under conditions effective to suppress glial scar formation in the subject.

93. The method according to claim 92, wherein the inhibitor is administered as a protein or polypeptide.

94. The method according to claim 92, wherein the inhibitor is administered as a nucleic acid construct encoding the inhibitor.

95. The method according to claim 94, wherein the nucleic acid construct is in a viral vector.

96. The method according to claim 95, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

97. The method according to claim 94, wherein the nucleic acid construct comprises a constitutive promoter for controlling expression of the inhibitor.

98. The method according to claim 94, wherein the nucleic acid construct further comprises a cell-specific promoter for controlling expression of the inhibitor.

99. The method according to claim 94, wherein the nucleic acid construct further comprises an inducible or conditional promoter for controlling expression of the inhibitor.

100. The method according to claim 92, wherein the inhibitor is noggin with its heparin binding site removed.

101. The method of introducing a therapeutic protein into a subject'"'"'s brain and spinal cord, said method comprising:

introducing a nucleic acid molecule encoding the therapeutic protein into the subject'"'"'s ependyma;

expressing the protein from the nucleic acid molecule within the subject'"'"'s ependyma; and

permitting the expressed protein to migrate within the subject'"'"'s brain and spinal cord.

102. The method according to claim 101, wherein the nucleic acid molecule is in a viral vector.

103. The method according to claim 102, wherein the viral vector is an adenoviral vector, a lentiviral vector, a retroviral vector, an adeno-associated viral vector, or a combination thereof.

104. The method according to claim 102, wherein the viral vector further comprises a constitutive promoter for controlling expression of the nucleic acid molecule.

105. The method according to claim 102, wherein the viral vector further comprises a cell-specific promoter for controlling expression of the nucleic acid molecule.

106. The method according to claim 102, wherein the viral vector further comprises an inducible or conditional promotor for controlling expression of the nucleic acid molecule.