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

• US 20070110698A1
• Filed: 07/15/2005
• Published: 05/17/2007
• Est. Priority Date: 10/20/1997
• Status: Abandoned Application

• Current Assignee: Elizabeth Wang
• Original Assignee: Elizabeth Wang
• Inventors: Wang, Elizabeth
• Application Number:
  US11/182,691
• Publication Number:
  US 20070110698A1
• Time in Patent Office: Days
• US Class Current: 424/70.140
• 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

One aspect of the present application relates to a method for modulating the growth state of an epithelial cell by ectopically contacting the epithelial cell, in vitro or in vivo, with a hedgehog therapeutic or ptc therapeutic in an amount effective to alter the rate (promote or inhibit) of proliferation of the epithelial cell, 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 an epithelial tissue, such as for inducing the formation of skin or other cutaneous tissue, or for inducing growth of hair.

Claims

1-68. -68. (canceled)

69. A method for promoting wound healing, comprising administering to a mammal in need thereof an amount of an agent effective to promote wound healing of said mammal in need thereof, wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and wherein the hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from

(i) binding to patched;

(ii) altering 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.

70. The method of claim 69, wherein the agent is a hedgehog agonist.

71. The method of claim 69, wherein the agent is a patched antagonist.

72. The method of claim 69, wherein the hedgehog agonist is a peptidomimetic of a hedgehog polypeptide sequence.

73. The method of claim 69, wherein the hedgehog agonist is a polypeptide including a hedgehog polypeptide sequence of at least a bioactive extracellular portion of a hedgehog protein.

74. The method of claim 73, wherein the polypeptide includes at least 50 contiguous amino acids residues of an N-terminal half of the hedgehog protein.

75. The method of claim 73, wherein the polypeptide includes at least 100 contiguous amino acids of an extracellular domain of the hedgehog protein.

76. The method of claim 73, wherein the polypeptide includes at least a 19 kd fragment of an extracellular domain of the hedgehog protein.

77. The method of claim 73, wherein the hedgehog protein is modified with one or more lipophilic or hydrophobic moieties.

78. The method of claim 73, wherein the hedgehog polypeptide is modified with one or more sterol moieties.

79. The method of claim 78, wherein the sterol moiety is cholesterol.

80. The method of claim 77, wherein the one or more lipophilic moieties are one or more fatty acid moieties.

81. The method of claim 80, wherein each fatty acid moiety is independently selected from myristoyl, palmitoyl, stearoyl, or arachidoyl.

82. The method of claim 80, wherein the hedgehog polypeptide is modified with one or more aromatic hydrocarbons.

83. The method of claim 69, wherein the method promotes healing of a wound resulting from surgery, burn, inflammation, or irritation.

84. The method of claim 83, wherein the surgery is cosmetic surgery.

85. The method of claim 69, wherein the agent is administered as a pharmaceutical composition.

86. The method of claim 69, wherein administering comprises contacting skin of the mammal in need thereof with a topical formulation comprising the composition.

87. The method of claim 86, wherein the composition is formulated for topical application on a sponge, bandage, dressing, or film.

107. The method of claim 69, wherein the method promotes wound healing with less scarring.

109. The method of claim 69, wherein the method is used in conjunction with a skin graft.

88. A method for promoting wound healing, comprising contacting skin of a mammal in need thereof with a composition comprising an amount of an agent effective to promote wound healing of said mammal in need thereof, wherein the agent is a hedgehog agonist or a patched antagonist that promotes hedgehog signal transduction, and wherein the hedgehog agonist or patched antagonist promotes hedgehog signal transduction by a mechanism selected from

(i) binding to patched;

(ii) altering 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.

89. The method of claim 88, wherein the composition is a pharmaceutical composition.

90. The method of claim 88, wherein the composition is formulated for topical application.

91. The method of claim 90, wherein the composition is formulated for topical application on a sponge, bandage, dressing, or film.

92. The method of claim 88, wherein the agent is a hedgehog agonist.

93. The method of claim 88, wherein the agent is a patched antagonist.

94. The method of claim 88, wherein the hedgehog agonist is a peptidomimetic of a hedgehog polypeptide sequence.

95. The method of claim 88, wherein the hedgehog agonist is a polypeptide including a hedgehog polypeptide sequence of at least a bioactive extracellular portion of a hedgehog protein.

96. The method of claim 95, wherein the polypeptide includes at least 50 contiguous amino acids residues of an N-terminal half of the hedgehog protein.

97. The method of claim 95, wherein the polypeptide includes at least 100 contiguous amino acids of an extracellular domain of the hedgehog protein.

98. The method of claim 95, wherein the polypeptide includes at least a 19 kd fragment of an extracellular domain of the hedgehog protein.

99. The method of claim 95, wherein the hedgehog protein is modified with one or more lipophilic or hydrophobic moieties.

100. The method of claim 95, wherein the hedgehog polypeptide is modified with one or more sterol moieties.

101. The method of claim 100, wherein the sterol moiety is cholesterol.

102. The method of claim 99, wherein the one or more lipophilic moieties are one or more fatty acid moieties.

103. The method of claim 102, wherein each fatty acid moiety is independently selected from myristoyl, palmitoyl, stearoyl, or arachidoyl.

104. The method of claim 102, wherein the hedgehog polypeptide is modified with one or more aromatic hydrocarbons.

105. The method of claim 88, wherein the method promotes healing of a wound resulting from surgery, burn, inflammation, or irritation.

106. The method of claim 105, wherein the surgery is cosmetic surgery.

108. The method of claim 88, wherein the method promotes wound healing with less scarring.

110. The method of claim 88, wherein the method is used in conjunction with a skin graft.