WO2003049700B1 - Growth hormone releasing hormone suplementation for treating chronically ill subjects - Google Patents

Growth hormone releasing hormone suplementation for treating chronically ill subjects

Info

Publication number
WO2003049700B1
WO2003049700B1 PCT/US2002/039509 US0239509W WO03049700B1 WO 2003049700 B1 WO2003049700 B1 WO 2003049700B1 US 0239509 W US0239509 W US 0239509W WO 03049700 B1 WO03049700 B1 WO 03049700B1
Authority
WO
WIPO (PCT)
Prior art keywords
ghrh
seqid
canceled
subject
biological equivalent
Prior art date
Application number
PCT/US2002/039509
Other languages
French (fr)
Other versions
WO2003049700A2 (en
WO2003049700A3 (en
Inventor
Ruxandra Draghia-Akli
Robert H Carpenter
Douglas R Kern
Robert J Schwartz
Glen King
Kevin Hahn
Malcolm K Brenner
Original Assignee
Advisys Inc
Baylor College Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Advisys Inc, Baylor College Medicine filed Critical Advisys Inc
Priority to AU2002357143A priority Critical patent/AU2002357143B2/en
Priority to BR0214869-2A priority patent/BR0214869A/en
Priority to MXPA04005713A priority patent/MXPA04005713A/en
Priority to CA2469310A priority patent/CA2469310C/en
Priority to EP02804771.0A priority patent/EP1465654B1/en
Publication of WO2003049700A2 publication Critical patent/WO2003049700A2/en
Publication of WO2003049700A3 publication Critical patent/WO2003049700A3/en
Publication of WO2003049700B1 publication Critical patent/WO2003049700B1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF] (Somatoliberin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Abstract

The present invention pertains to compositions and methods for plasmid-mediated supplementation. The compositions and method are useful for retarding the growth of the tumor, and retarding cachexia, wasting, anemia and other effects that are commonly associated in cancer bearing animals. Overall, the embodiments of the invention can be accomplished by delivering an effective amount of a nucleic acid expression construct that encodes a GHRH or functional biological equivalent thereof into a tissue of an animal and allowing expression of the encoded gene in the animal. For example, when such a nucleic acid sequence is delivered into the specific cells of the animal tissue specific constitutive expression is achieved. Furthermore, external regulation of the GHRH or functional biological equivalent thereof gene can be accomplished by utilizing inducible promoters that are regulated by molecular switch molecules, which are given to the animal. The preferred method to deliver the constitutive or inducible nucleic acid encoding sequences of GHRH or the functional biological equivalents thereof is directly into the cells of the animal by the process of in vivo electroporation. In addition, a treatment for retarding the growth of the tumor, and retarding cachexia or the wasting effects that are commonly associated with tumors is achieved by the delivery of recombinant GHRH or biological equivalent into the animal.

Claims

AMENDED CLAIMS and STATEMENT
[Received by the International Bureau on 16 September 2003 (16.09.03): original claims 1-386 replaced by amended claims 1-386]
1. A method of treating anemia in a subject, comprising: delivering into cells of the subject an effective amount of a nucleic acid expression construct that encodes a growth- hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof.
2. The method of claim 1, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising electroporating the cells.
3. The method of claim 1, wherein the cells of the subject are somatic cells, or stem cells.
4. The method of claim 1, wherein the nucleic acid expression construct comprises SEQID#11, SBQID#12, SEQID#13, SEQID^, SEQ1D#17, SEQID#18, SEQTD#19, SEQlD#20, oτ SEQlD#21.
5. The method of claim 1, wherein the nucleic acid expression construct further comprises, a traπsfection-facilitating polypeptide.
6. The method of claim 5, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
7. The method of claim 5, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
8. The method of claim 1 , wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
9. The method of claim 8, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject. 138
10. The method of claim 9, wherein the tissue specific cells of the subject comprises muscle cells.
11. The method of claim 8, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
12. The method of claim 8, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEQ1D #6):
-X.1-Xj-DArFTNSYRKV -Xi-Q SARKLlJQDI-X4-Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or -isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V")> or isoleucine
("i");
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomer of the amino acid methionine ("M")> or leucine C'L")! X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine {"N") or a combination thereof.
13. The method of claim 1, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQID#1, SEQID#2, SEQID#3, or SEQID#4.
14. The method of claim 1, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
15. Cancel ed.
16. Canceled.
17. Canceled.
18. Canceled.
19. Canceled.
20. Canceled.
21. Canceled.
22. Canceled.
23. Canceled.
24. Canceled.
25. Canceled.
26. Canceled.
141
27. Canceled.
28. Canceled.
29. Canceled.
30. A method of treating anemia in a subject, comprising: delivering into the subject a recombinant growth-hormone-releasing-hormone ("GHRH") or a biological functional equivalent thereof.
31. The method of claim 30, wherein the recombinant GHRH is a biologically active polypeptide; and the recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
142
32. The method of claim 30, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X^-Xz-DAIFraSY^KV -Xa-QLSARKLLQDI-^-Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
Xz is a D-or L-isomer of tbe amino acid alanine ("A"), valine CN"), or isoleucine ("I");
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
Xt is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine ("Ν"); or a combination thereof.
33. The method of claim 30, wherein the recombinant GHRH or functional biological equivalent thereof is of a formula comprising SEQED#1, SEQID#2, SEOTD#3, or SEQID#4.
34." The method of claim 30, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
35. A method of increasing total red blood cell mass in a subject, comprising: delivering into cells of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-rcleasing-hormone ("GHRH") or functional biological equivalent thereof.
36. The method of claim 35, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising electroporating the cells.
37. The method of claim 35, wherein the cells of the subject are somatic cells, or stem cells. 143
38. The method of claim 35, wherein the nucleic acid expression construct comprises SEQID#11, SEQID#12, SEQID#13, SEQTD#14, SEQ1D#17, SEQID#18, SEQID#19, SEQID#20, or SEQID#21.
39. The method of claim 35, wherein the nucleic acid expression construct further comprises, a transfection-facilitating polypeptide.
40. The method of claim 39, wherein the transfection-facihtating polypeptide comprises a charged polypeptide.
41. The method of claim 39, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
42. The method of claim 35, wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
43. The method of claim 42, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject.
44. The method of claim 43, wherein the tissue specific cells of the subject comprises muscle cells.
45. The method of claim 42, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 144
46. The method of claim 42, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X-λ-X2-DAIFTNSYRKVL-Xi-QLSARKLLQDI -X1-X5-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine {"A"), valine C'V"), or isoleucine ("F);
Xa is a D-or L-isomcr of the amino acid alanine ("A") or glycine ("G");
XΛ is a D-or L-isomcr of the amino acid methionine ("M"), or leucine ("L");
Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N")J or a combination thereof.
47. The method of claim 35, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQID#1, SEQED#2, SEQID#3, or SEQID#4.
48. The method of claim 35, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
145
49. Canceled,
50. Canceled.
51. Canceled.
52. Canceled.
53. Canceled.
54. Canceled.
55. Canceled.
146
56. Canceled.
57. Canceled.
58. Canceled.
59. Canceled.
60. Canceled.
147
61. Canceled.
62. Canceled.
63. Canceled.
64. A method of increasing total red blood cell mass in a subject, comprising: delivering into the subject a recombinant growth-hoπnone-releasing-hormone ("GHRH") or a biological functional equivalent thereof.
65. The method of claim 64, wherein the recombinant GHRH is a biologically active polypeptide; and the recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
148
66. The method of claim 64, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQ1D #6):
-X.j-X2-DAIFTNSYRKVL-X3-QLSARKI.LQDI -X. -X5-RQQGER QEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ON"), or isoleucine CH;
X3 is a D-or L-isomer of the amino acid alanine ("A") <>r glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("Ν"); or a combination thereof.
67. The method of claim 64, wherein the recombinant GHRH or functional biological equivalent thereof is of a formula comprising SEQE>#1, SEQID#2, SEQTD#3, or SEQ1D#4.
68. The method of claim 64, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
69. A method to reverse wasting in a subject, comprising: delivering into cells of the subject an effective amount of a nucleic acid expression construct that encodes a growfh- hormone-relcasing-hormone ("GHRH") or functional biological equivalent thereof.
70. The method of claim 69, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising electroporating the cells.
71. The method of claim 69, wherein the cells of the subject are somatic cells, or stem cells. 149
72. The method of claim 69, wherein the nucleic acid expression construct comprises SEQID#11, SEQrD#l2, SEQ1D#13, SEQID#14, SEQID#17, SEQID#18, SEQ1D#19, SEQID#20, or SEQTD#21.
73. The method of claim 69, wherein the nucleic acid expression construct further comprises, a transfection-facilitating polypeptide.
74. The method of claim 73, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
75. The method of claim 73, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
76. The method of claim 69, wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
77. The method of claim 76, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject.
78. The method of claim 77, wherein the tissue specific cells of the subject comprises muscle cells,
79. The method of claim 76, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 150
80. The method of claim 76, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X.ι-Xs-DAIFT SYRKVL-X3H3LSARKLLQDI -X4-X5-RQQGERNQEQGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V), or isoleucine
(T);
X3 is a D-or L-isomer of the arnino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomer of the amino acid methionine ("M")> or leucine ("L"); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
81. The method of claim 69, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEOTD#l, SEQID#2, SEQID#3, or SEQID#4.
82. The method of claim 69, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
83. Canceled.
84. Canceled.
85. Canceled.
86. Canceled.
87. Canceled.
88. Canceled.
89. Canceled.
152
90. Canceled.
91. Canceled.
92. Canceled.
93. Canceled.
94. Canceled.
153
95. Canceled.
96. Canceled.
97. Canceled.
98. A method to reverse wasting in a subject, comprising: delivering into the subject a recombinant growth-hormone-releasmg-hormone ("GHRH") or a biological functional equivalent thereof.
99. The method of claim 98, wherein the recombinant GHRH is a biologically active polypeptide; and me recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
154
100. The method of claim 98, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X.i-Xa-DAIFTOSYRKVL-Xa-QLSARKLLQDI-XLi-Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine ("I");
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
101. The method of claim 100, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
102. The method of claim 98, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH') secretion in the subject.
103. A method to reverse abnormal weight loss in a subject, comprising: delivering into cells of the subject an effective amount of a nucleic acid expression construct that encodes a growtb-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof.
104. The method of claim 103, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising elcctroporating the cells.
105. The method of claim 103, wherein the cells of the subject are somatic cells, or stem cells. 155
106. The method of claim 103, wherein the nucleic acid expression construct comprises SEQUWrl SEQID#12, SEQID#13, SEQID#14, SEQ1D#17, SEQ1D#18, SEQID#19, SEQID#20, or SEQID#21.
107. The method of claim 103, wherein the nucleic acid expression construct further comprises, a transfection-facilitating polypeptide.
108. The method of claim 107, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
109. The method of claim 107, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
110. The method of claim 103, wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
111. The method of claim 107, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject.
112. The method of claim 111, wherein the tissue specific cells of the subject comprises muscle cells.
113. The method of claim 107, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 156
114. The method of claim 107, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEO D #6):
-X-ι-Xa-DAIFTNSΫRKVL-Xs"-QLSARKLLQDl-X4-Xs-RQQGERNQEQGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine
C ");
X3 is a D-or L-isomcr of the amino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L"); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine CN"); or a combination thereof.
1 1 . The method of claim 103, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQID#1, SEQID#2, SEQID#3, or SEQ1D#4.
116. The method of claim 103, wherein the encoded GHRH or functional biological equivalent thereof facilitates grow hormone ("GH") secretion in the subject.
157
117. Canceled.
118. Canceled.
119. Canceled.
120. Canceled.
121. Canceled.
122. Canceled.
123. Canceled.
158
124. Canceled.
125. Canceled.
126. Canceled.
127. Canceled,
128. Canceled.
159
129. Canceled.
130. Canceled.
131. Canceled.
132. A method of increasing weight gain in a chronicalJy ill subject, comprising: delivering into the chronically ill subject a recombinant growth-hoπrtone-releasing-hormone ("GHRH") or a biological functional equivalent thereof.
133. The method of claim 132, wherein the recombinant GHRH is a biologically active polypeptide; and the recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
160
134. The method of claim 132, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X-i-X.-DAIFTNSY lKVL-Xj-QLSARKLLQDI -X^-Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine CΥ"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine ry.
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomer of the arnino acid methionine ("M"), or leucine ("L"); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
135. The method of claim 132, wherein the recombinant GHRH or functional biological equivalent thereof is of a formula comprising SEQTD#1, SEQTD#2, SEQID#3, or SEQID#4.
136. The method of claim 132, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the chronically ill subject.
137. A method to reverse the suppression of lymphopoesis in a subject, comprising: delivering into cells of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hor one-releasing-hormone ("GHRH") or functional biological equivalent thereof.
138. The method of claim 137, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising electroporating the cells.
139. The method of claim 137, wherein the cells of the subject are somatic cells, or stem cells. 161
140. The method of claim 137, wherein the nucleic acid expression construct comprises SEQID#11, SEQID#12, SEQ1D#13, SEQID#14, SEQ1D#17, SEQID#18, SEQ1D#19, SEQlD#20, o SEQID#21.
141. The method of claim 137, wherein the nucleic acid expression construct further comprises, a transfection-facilitating polypeptide.
142. The method of claim 141, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
143. The method of claim 141, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
144. The method of claim 137, wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
145. The method of claim 144, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject.
146. The method of claim 145, wherein the tissue specific cells of the subject comprises muscle cells.
147. The method of claim 144, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 162
148. The method of claim 144, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEQID #6):
-X.3.-X2-DAIFTNSYRKVL-X3-QLSARKLLQDI-X4-XΪ-RQQGERNQEQGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine {"A"), valine ("V"), or isoleucine
CT ;
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); X) is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L"); X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
149. The method of claim 137, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQID#1, SEQID#2, S£QΪD#3, or SEQJD#4.
150. The method of claim 137, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
163
151. Canceled,
152. Canceled.
153. Canceled.
154. Canceled.
155. Canceled.
156. Canceled.
157. Canceled.
164
158. Canceled.
159. Canceled.
160. Canceled.
161. Canceled.
162. Caπcele
165
163. Canceled.
164. Canceled.
165. Canceled.
166. A method to reverse the suppression of lymphopoesis in a subject, comprising: delivering into the subject a recombinant growth-hormone-releasing-hormone ("GHRH") or a biological functional equivalent thereof.
167. The method of claim 166, wherein the recombinant GHRH is a biologically active polypeptide; and the recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
166
168. The method of claim 166, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQ1D #6):
-X,λ-Xi-DAIFTNSYRKVL-X,-QLSARKL QDI-X4-X5-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine "D;
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
X» is a D-or L-isomer of the amino acid melM<)nine (" "), or leucine ("L");
X5 is a D-or L-isomer of the cLmino acid serine ("S") or asparagine ("N"); or a combination thereof.
169. The method of claim 166, wherein the recombinant GHRH or functional biological equivalent thereof is of a formula comprising SEQ1D#1, S£QID#2, SEOJD#3, or SEQID#4.
170. The method of claim 166, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH') secretion in the subject.
171. A method of treating immune dysfunction in a subject, comprising: delivering into ceils of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof.
172. The method of claim 171, wherein delivering into the cells of the subject the nucleic acid expression construct further comprising clectroporating the cells.
173. The method of claim 171, wherein the cells of the subject are somatic cells, or stem cells. 167
174. The method of claim 171, wherein the nucleic acid expression construct comprises SEQID#11, SEQID#12, SEQID#13, SEQ1D#14, SEQID#17, SEQ1D#18, SEQID#19, SEQΪD#20, or SEQ1D#21.
175. The method of claim 171, wherein the nucleic acid expression construct further comprises, a transfcction-facihtating polypeptide.
176. The method of claim 175, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
177. The method of claim 175, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
178. The method of claim 171, wherein delivering into the cells of the subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
179. The method of claim 178, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the subject.
180. The method of claim 179, wherein the tissue specific cells of the subject comprises muscle cells.
181. The method of claim 178, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct arnino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 168
182. The method of claim 178, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEOTD #6):
-X.1-Xa-DArFT SYR VL-XsH2LSARKLLQDI-X4-X.-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine {"Y"), or histidine ("H");
Xι is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine ("1");
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
Xs is a D-or L-isomer of the arnino acid serine ("S") or asparagine ("N"); or a combination thereof.
183. The method of claim 171, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQTD#1, SEQTD#2, SEQID#3, or SEQID#4.
184. The method of claim 171, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
169
185. Canceled
186. Canceled.
187. Canceled.
188. Canceled.
189. Canceled.
190. Canceled.
191. Canceled.
170
192. Canceled.
193. Canceled.
194. Canceled.
195. Canceled.
196. Canceled.
171
197. Canceled.
198. Canceled.
199. Canceled.
200. A method of treating immune dysfunction in a subject, comprising: delivering into the subject a recombinant growth-hormone-releasing-hormone ("GHRH") or a biological functional equivalent thereof.
201. The method of claim 200, wherein the recombinant GHRH is a biologically active polypeptide; and the recombinant functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide.
172
202. The method of claim 200, wherein the recombinant GHRH or functional biological equivalent thereof is of formula (SEQTD #6):
-X.1-X2-DAIFTNSYRKVL-X3-QLSARKLLQDI -X4-X5-RQQQERNQECjGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V), or isoleucine CT');
Xa is a D-or L-isomer of the arnino acid alanine ("A") or glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine (" ");
X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
203. The method of claim 200, wherein the recombinant GHRH or functional biological equivalent thereof is of a formula comprising SEQJD#1, SEQID#2, SEQID#3, or SEQTD#4.
204. The method of claim 200, wherein the recombinant GHRH or functional biological equivalent thereof facilitates growth hormone ("GH*) secretion in the subject.
205. A method to extend life expectancy for a chronically ill subject, comprising: delivering into cells of the chronically ill subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof.
206. The method of claim 205, further comprising electroporating the cells.
207. The method of claim 205, wherein the cells of the chronically ill subject are somatic cells, or stem cells. 173
208. The method of claim 205, wherein the nucleic acid expression construct comprises SEQ1D#11, SEQID#12, S£QID#13, SEQID#14, SEQID#17, SEQID#18, SEQID#19, SEQID#20, or SEQ1D#21.
209. The method of claim 205, wherein the nucleic acid expression construct further comprises, a transfection-facilitating polypeptide.
210. The method of claim 209, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
211. The method of claim 209, wherein the trar-sfection-facilitating polypeptide comprises poly-L-glutamate.
212. The method of claim 205, wherein delivering into the cells of the chronically ill subject the nucleic acid expression construct initiates expression of the encoded GHRH or functional biological equivalent thereof.
213. The method of claim 212, wherein the encoded GHRH or functional biological equivalent thereof is expressed in tissue specific cells of the chronically ill subject.
214. The method of claim 213, wherein the tissue specific cells of the chronically ill subject comprises muscle cells.
215. The method of claim 212, wherein the encoded GHRH is a biologically active polypeptide; and the encoded functional biological equivalent of GHRH is a polypeptide that has been engineered to contain a distinct amino acid sequence while simultaneously having similar or improved biologically activity when compared to a wild-type GHRH polypeptide. 174
216. The method of claim 212, wherein the encoded GHRH or functional biological equivalent thereof is of formula (SEQflD #6):
-X.1-Xj-DAIFTNSYR VL-Xs-«LSARKLLQDI-X4-X5-RQQGEHNQEQGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine
CD;
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); Xt is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L"); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine (" "); or a combination thereof.
217. The method of claim 205, wherein the nucleic acid expression construct encodes a polypeptide of a sequence comprising SEQΪD#1, SEQ1D#2, SEQID#3, or SEQID#4.
218. The method of claim 205, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the chronically ill subject.
175
219. Canceled.
220. Canceled.
221. Canceled.
222. Canceled.
223. Canceled.
224. Canceled.
225. Canceled.
176
226. Canceled.
227. Canceled.
228. Canceled.
229. Canceled.
230. Canceled.
177
231. Canceled.
232. Canceled.
233. Canceled.
234. Canceled.
235. Canceled.
178
236. Canceled.
237. Canceled.
238. Canceled.
239. A method for treating a subject having a tumor, the tumor being selected from a group consisting of adenoma; mast cell tumor; melanoma; sarcoma; or solid tumor; the method comprising: delivering into a tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-bormone-releasirig-hormone ("GHRH") or functional biological equivalent thereof; wherein subsequent expression of the GHRH or biological equivalent is sufficient to retard the growth of the tumor.
179
240. The method of claim 239, further comprising: applying a cejl-transfecting pulse to the tissue; wherein, the cell-transfecting pulse is delivered to an area in the tissue comprising the delivered nucleic acid expression construct.
241. The method of claim 240, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes.
242. The method of claim 240, wherein the cell-transfecting pulse is an electrical pulse or a vascular pressure pulse.
243. The method of claim 239, wherein delivering into a tissue of the subject the nucleic acid expression construct further comprising electroporating the cells.
244. The method of claim 239, wherein delivering is by injection, gene gun, or gold particle bombardment.
245. The method of claim 239, wherein the subject is a domesticated animal; a food animal; or a work animal.
246. The method of claim 239, wherein the subject is a human.
247. The method of claim 239, wherein the nucleic acid expression construct is substantially free of a viral backbone.
248. The method of claim 239, wherein a promoter of the nucleic acid expression construct comprises a tissue-specific promoter.
249. The method of claim 248, wherein the tissue-specific promoter comprises a muscle-specific promoter. 180
250. The construct of claim 248, wherein the promoter comprises SPc5-12.
251. The method of claim 239, wherein a 3' untranslated region of the nucleic expression construct is a human growth hormone 3' UTR, bovine growth hormone 3' UTR, skeletal alpha actin 3 ' UTR, or SV40 polyadenylatioD signal.
252. The method of claim 239, wherein the tissue comprises muscle.
253. The method of claim 239, wherein the nucleic acid expression construct is SEQTD#11, SEQID#12, SEQfD#13, SEQTD#14, SEQID#17, SEQID#18, SEQID#19, SEQTD#20, or SEQ1D#21.
254. The method of claim 239, wherein the encoded GHRH or functional biological equivalent comprises SEQID#1.
255. The method of claim 239, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#2.
256. The method of claim 239, wherein the encoded GHRH or functional biological equivalent comprises SEQID#3.
257. The method of claim 239, wherein the encoded GHRH or functional biological equivalent comprises SEQID#4.
258. The method of claim 239, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#10.
181
259. The method of claim 239, wherem the encoded GHRH or functional biological equivalent thereof comprises the amino acid formula (SEQ 1D#6):
-X.i-Xz-DAIF'raSTOKVL-Xs-^LSARKLLQDI-X.-Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xx is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H');
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine CN"). or isoleucine
CO;
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("Ν")j °r a combination thereof.
260. The method of claim 239, wherein the nucleic acid expression construct further comprises a transfection-faciUtating polypeptide.
261. The method of claim 259, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
262. The method of claim 259, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
263. The method of claim 239, wherein the encoded functional biological equivalent of GHRH is a polypeptide having similar or improved biological activity when compared to a wild- type GHRH polypeptide.
264. The method of claim 239, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject. 182
265. The method of claim 239, wherein the tumor comprises a benign or malignant tumor.
266. The method of claim 239, wherein kidney failure is prevented in the subject.
267. A method for treating a subject having a carcinoma; the method comprising: delivering into a tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof;
wherein subsequent expression of the GHRH or biological equivalent is sufficient to retard the growth of the carcinoma.
268. The method of claim 267, further comprising: applying a cell-transfecting pulse to the tissue; wherein, the cell-transfecting pulse is delivered to an area in the tissue comprising the delivered nucleic acid expression construct.
269. The method of claim 268, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes.
270. The method of claim 268, wherein the ceJl-transfecting pulse is an electrical pulse or a vascular pressure pulse.
271. The method of claim 267, wherein delivering into a tissue of the subject the nucleic acid expression construct further comprising electroporating the cells.
272. The method of claim 267, wherein delivering is by injection, gene gun, or gold particle bombardment. 183
273. The method of claim 267, wherein the subject is a domesticated animal; a food animal; or a work animal.
274. The method of claim 267, wherein the subject is a human.
275. The method of claim 267, wherein the nucleic acid expression construct is substantially free of a viral backbone.
276. The method of claim 267, wherein a promoter of the nucleic acid expression construct comprises a tissue-specific promoter.
277. The method of claim 276, wherein the tissue-specific promoter comprises a muscle-specific promoter.
278. The construct of claim 276, wherein the promoter comprises SPc5-12.
279. The method of claim 267, wherein a 3' untranslated region of the nucleic expression construct is a human growth hormone 3' UTR, bovine growth hormone 3' UTR, skeletal alpha actin 3' UTR, or SV40 polyadcnylation signal.
280. The method of claim 267, wherein the tissue comprises muscle.
281. The method of claim 267, wherein the nucleic acid expression construct is SEQID#11, SEQID#12, SEOTD#13, SEQID#14, SEQTD#17, SEQID#18, SEQID#19, SEQID#20, or SEQ1D#21.
282. The method of claim 267, wherein the encoded GHRH or functional biological equivalent comprises SEQTD#1.
283. The method of claim 267, wherein the encoded GHRH or functional biological equivalent comprises SEQID#2.
284. The method of claim 267, wherein the encoded GHRH or functional biological equivalent comprises SEQID#3. 184
285. The method of claim 267, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#4.
286. The method of claim 267, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#10.
287. The method of claim 267, wherein the encoded GHRH or functional biological equivalent thereof comprises the amino acid formula (SEQ ID#6):
-X.1-X2-DAIFTNSYRKVL-X3H2LSARKLLQDI - -Xs-RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine CN"), or isoleucine CT); 3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); 4 is a D-or L-isomer of the amino acid methionine CM"), or leucine ("L");
Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine (" "); or a combination thereof.
288. The method of claim 267, wherein the nucleic acid expression construct further comprises a transfection-facilitating polypeptide.
289. The method of claim 287, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
290. The method of claim 287, wherein the transfection-facilitating polypeptide comprises poly-L-gl tamate.
291. The method of claim 267, wherein the encoded functional biological equivalent of GHRH is a polypeptide having similar or improved biological activity when compared to a wild- type GHRH polypeptide. 185
292. The method of claim 267, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
293. The method of claim 267, wherein the carcinoma comprises a benign or malignant carcinoma.
294. A method for treating a subject having a leukemia or a lymphoma; the method comprising: delivering into a tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof; wherein subsequent expression of the GHRH or biological equivalent is sufficient to retard the growth rate of the leukemia or the lymphoma.
295. The method of claim 294, further comprising: applying a cell-transfecting pulse to the tissue; wherein, the cell-transfecting pulse is delivered to an area in the tissue comprising the delivered nucleic acid expression construct.
296. The method of claim 295, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes.
297. The method of claim 295, wherein the cell-transfecting pulse is an electrical pulse or a vascular pressure pulse.
298. The method of claim 294, wherein delivering into a tissue of the subject the nucleic acid expression construct further comprising electroporating the cells.
299. The method of claim 294, wherein delivering is by injection, gene gun, or gold particle bombardment. 186
300. The method of claim 294, wherein the subject is a domesticated animal; a food animal; or a work animal.
301. The method of claim 294, wherein the subject is a human.
302. The method of claim 294, wherein the nucleic acid expression construct is substantially free of a viral backbone.
303. The method of claim 294, wherein a promoter of the nucleic acid expression construct comprises a tissue-specific promoter.
304. The method of claim 303, wherein the tissue-specific promoter comprises a muscle-specific promoter.
305. The construct of claim 303, wherein the promoter comprises SPc5-12.
306. The method of claim 294, wherein a 3' untranslated region of the nucleic expression construct is a human growth hormone 3' UTR, bovine growth hormone 3' UTR, skeletal alpha actin 3' UTR, or SV40 polyadenylation signal.
307. The method of claim 294, wherein the tissue comprises muscle.
308. The method of claim 294, wherem the nucleic acid expression construct is SEQ1D#11, SEQID#12, SEQID#13, SEQ1D#14, SEQ_D#17, SEQID#18, SEQID#19, SEQID#20, or SEQID#21.
309. The method of claim 294, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#1.
310. The method of claim 294, wherein the encoded GHRH or functional biological equivalent comprises SEQID#2.
311. The method of claim 294, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#3. 187
312. The method of claim 294, wherein the encoded GHRH or functional biological equivalent comprises SEQID#4.
313. The method of claim 294, wherein the encoded GHRH or functional biological equivalent comprises SEQID#10.
314. The method of claim 294, wherein the encoded GHRH or functional biological equivalent thereof comprises the amino acid formula (SEQ 1D#6):
-X-ι-Xj-DAlFTNSYRI VL-X3^LSAKKLLQDI -Xj-X5--RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("N")ι or isoleucine ("1");
Xi is a D-or L-isomcr of the amino acid alanine ("A") or glycine ("G");
Xt is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
X5 is a D-or L-isomer of the amino acid serine ("S") or asparagine CΝ"); or a combination thereof,
315. The method of claim 294, wherein the nucleic acid expression construct further comprises a transfection-facilitating polypeptide.
316. The method of claim 315, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
317. The method of claim 315, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
318. The method of claim 294, wherein the encoded functional biological equivalent of GHRH is a polypeptide having similar or improved biological activity when compared to a wild- type GHRH polypeptide. 188
319. The method of claim 294, wherem the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject.
320. A method for preventing the development of a etastatic-tumor in a subject, comprising: delivering into a tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-hormone ("GHRH") or functional biological equivalent thereof;
wherein subsequent expression of the GHRH or biological equivalent is sufficient to retard the development of the metastatic-tumor.
321. The method of claim 320, further comprising: applying a cell-transfecting pulse to the tissue; wherein, the cell-transfecting pulse is delivered to an area in the tissue comprising the delivered nucleic acid expression construct.
322. The method of claim 321, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes.
323. The method of claim 321, wherein the cell-transfecting pulse is an electrical pulse or a vascular pressure pulse.
324. The method of claim 320, wherein delivering into a tissue of the subject the nucleic acid expression construct further comprising elecroporatiπg the cells.
325. The method of claim 320, wherein delivering is by injection, gene gun, or gold particle bombardment.
326. The method of claim 320, wherein the subject is a domesticated animal; a food animal; or a work animal. 189
327. The method of claim 320, wherein the subject is a human.
328. The method of claim 320, wherein the nucleic acid expression construct is substantially free of a viral backbone.
329. The method of claim 320, wherein a promoter of the nucleic acid expression construct comprises a tissue-specific promoter.
330. The method of claim 329, wherein the tissue-specific promoter comprises a muscle-specific promoter.
331. The construct of claim 329, wherein the promoter comprises SPc5- 12.
332. The method of claim 320, wherein a 3' untranslated region of the nucleic expression construct is a human growth hormone 3' UTR, bovine growth hormone 3' UTR, skeletal alpha actin 3' UTR, or SV40 polyadenylation signal.
333. The method of claim 320, wherein the tissue comprises muscle.
334. The method of claim 320, wherein the nucleic acid expression construct is SEQ1D#11, SEQ1D#12, SEQID#13, SEQID#14, SEQID#17, SEQ1D#18, SEQID#19, SEQJD#20, or SEQfD#21.
335. The method of claim 320, wherein the encoded GHRH or functional biological equivalent comprises SEQID#1.
336. The method of claim 320, wherein the encoded GHRH or functional biological equivalent comprises SEQID#2.
337. The method of claim 320, wherein the encoded GHRH or functional biological equivalent comprises SEQID#3.
338. The method of claim 320, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#4. 190
339. The method of claim 320, wherein the encoded GHRH or functional biological equivalent comprises SEQTD#10.
340. The method of claim 320, wherein the encoded GHRH or functional biological equivalent thereof comprises the amino acid formula (SEQ ID#6):
- X-i - a-D AI FT S YRKVL - X3-QLS ARKLLQD I - * - Xs-RQOGERNQEQGA - OH wherein the formula has the following characteristics:
Xj is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleυcine ("i");
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G");
X4 is a D-or L-isomer of the amino acid methionine ("M"), or leucine ("L");
Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
341. The method of claim 320, wherein the nucleic acid expression construct further comprises a transfection-facilitating polypeptide.
342. The method of claim 341, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
343. The method of claim 341, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
344. The method of claim 320, wherein the encoded functional biological equivalent of GHRH is a polypeptide having similar or improved biological activity when compared to a wild- type GHRH polypeptide.
345. The method of claim 320, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH") secretion in the subject. 191
346. The method of claim 320, wherein the carcinoma comprises a benign or malignant carcinoma.
347. A method for treating a subject having a metastatic growth of tumor cells, the tumor cells being selected from a group consisting of an adenoma; a carcinoma, a leukemia, a lymphoma, a mast cell tumor, a melanoma, a sarcoma, and a solid tumor, the method comprising:
(a) delivering into a muscle tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-bormone- releasing-bormone ("GHRH") or functional biological equivalent thereof;
(b) applying an eJectroporation cell-transfecting pulse to the tissue; wherein: the nucleic acid expression construct comprises: a muscle specific promoter; the encoded GHRH or functional biological equivalent thereof; and a human growth hormone 3' untranslated region ("3' UTR"); the promoter, the encoded GHRH or functional biological equivalent thereof, and the 3' untranslated region are operatively linked, the in vivo expression of the GHRH or biological equivalent is regulated by the promoter, and the construct is substantially free from a viral backbone; subsequent expression of the GHRH or biological equivalent facilitates growth hormone ("GH") secretion in the subject and is sufficient to retard the growth of the metastatic growth of cells.
348. The method of claim 347, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes. 192
349. The method of claim 347, wherein the subject is a domesticated animal; a food animal; or a work animal.
350. The method of claim 347, wherein the subject is a human.
351. The method of claim 347, wherein the nucleic acid expression construct is SEQID#11, SEQJD#12, SEQLD#13, SEQID#14, SEQfD#17, SEQ1D#18, SEQID#19, SEQJD#20, or SEQTD#21.
352. The method of claim 347, wherein the encoded GHRH or functional biological equivalent comprises SEQID#1.
353. The method of claim 347, wherein the encoded GHRH or functional biological equivalent comprises SEQID#2.
354. The method of claim 347, wherein the encoded GHRH or functional biological equivalent comprises SEQID#3.
355. The method of claim 347, wherein the encoded GHRH or functional biological equivalent comprises SEQID#4.
356. The method of claim 347, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#10.
193
357. The method of claim 347, wherein the encoded GHRH or functional biological equivalent thereof comprises the amino acid formula (SEQ 1D#6):
-X.l-X2-DAIFTNSYϊUCvL-X3^LSAR LLQDI-X.-Xs--RQ0^BRNQEQGA-0H wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y"), or histidine ("H");
X2 is a D-or L-isomer of the amino acid alanine ("A"), valine ("V"), or isoleucine
Figure imgf000058_0001
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomer of the amino acid methionine M"), or leucine (" "); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("N"); or a combination thereof.
358. The metliod of claim 347, wherein the nucleic acid expression construct further comprises a charged transfection-facilitating polypeptide, the charged transfection-facilitating polypeptide comprising poly-L-glutamate.
359. A method for treating kidney failure in a subject, the method comprising: delivering into a tissue of the subject an effective amount of a nucleic acid expression construct that encodes a growth-hormone-releasing-bormone ("GHRH*) or functional biological equivalent thereof; wherein subsequent expression of the GHRH or biological equivalent is sufficient to retard the growth of the carcinoma.
360. The method of claim 359, further comprising: applying a cell-transfecting pulse to the tissue; wherein, the cell-transfecting pulse is delivered to an area in the tissue comprising the delivered nucleic acid expression construct. 194
361. The method of claim 360, further comprising: placing a plurality of electrodes in the tissue before applying the cell-transfecting pulse to the tissue; wherein the nucleic acid expression construct is delivered to the tissue in an area that interposes the plurality of electrodes.
362. The method of claim 360, wherein the cell-transfecting pulse is an electrical pulse or a vascular pressure pulse.
363. The method of claim 359, wherein delivering into a tissue of the subject the nucleic acid expression construct further comprising electroporating the cells.
364. The method of claim 359, wherein delivering is by injection, gene gun, or gold particle bombardment.
365. The metliod of claim 359, wherein the subject is a domesticated animal; a food animal; or a work animal.
366. The method of claim 359, wherein the subject is a human.
367. The method of claim 359, wherem the nucleic acid expression construct is substantially free of a viral backbone.
368. The method of claim 359, wherein a promoter of the nucleic acid expression construct comprises a tissue-specific promoter.
369. The method of claim 368, wherein the tissue-specific promoter comprises a muscle-specific promoter.
370. The construct of claim 368, wherein the promoter comprises SPc5- 12. 195
371. The method of claim 359, wherein a 3' untranslated region of the nucleic expression construct is a human growth hormone 3' UTR, bovine growth hormone 3' UTR, skeletal alpha actin 3' UTR, or SV40 poiyadenylation signal.
372. The method of claim 359, wherein the tissue comprises muscle.
373. The method of claim 359, wherein the nucleic acid expression construct is SEQ1D#11, SEQID#12, SEQ1D#13, SEQID#14, SEQID#17, SEQID#18, S£QID#19, SEQID#20, or SEQID#2
374. The method of claim 359, wherein the encoded GHRH or functional biological equivalent comprises SEQID#1.
375. The method of claim 359, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#2.
376. The method of claim 359, wherein the encoded GHRH or functional biological equivalent comprises SEQ1D#3.
377. The method of claim 359, wherein the encoded GHRH or functional biological equivalent comprises SEQID#4.
378. The method of claim 359, wherein the encoded GHRH or functional biological equivalent comprises SEQID#10.
196
379. The method of claim 359, wherein the encoded GHRH or functional biological equivalent thereof comprises the arπino acid formula (SEQ 1D#6):
-X.1-X2-DAIF,raSYTlKVL-X3^LSARKLIJQDI -X4-X5--RQQGERNQEQGA-OH wherein the formula has the following characteristics:
Xi is a D-or L-isomer of the amino acid tyrosine ("Y")» °r histidine ("H');
X2 is a D-or L-isomcr of the amino acid alanine ("A"), valine CN"), or isoleucine
X3 is a D-or L-isomer of the amino acid alanine ("A") or glycine ("G"); X4 is a D-or L-isomcr of the amino acid methionine ("M"), or leucine ("L"); Xs is a D-or L-isomer of the amino acid serine ("S") or asparagine ("Ν"); or a combination thereof.
380. The method of claim 359, wherein the nucleic acid expression construct further comprises a transfection-facilitating polypeptide.
381. The method of claim 380, wherein the transfection-facilitating polypeptide comprises a charged polypeptide.
382. The method of claim 380, wherein the transfection-facilitating polypeptide comprises poly-L-glutamate.
383. The method of claim 359, wherein the encoded functional biological equivalent of GHRH is a polypeptide having similar or improved biological activity when compared to a wild- type GHRH polypeptide.
384. The method of claim 359, wherein the encoded GHRH or functional biological equivalent thereof facilitates growth hormone ("GH') secretion in the subject. 197
385. The method of claim 359, wherein the kidney failure resulted from the subject having a cancer selected from a group consisting of adenoma; carcinoma, leukemia, lymphoma, mast cell tumor; melanoma; sarcoma; or solid tumor.
386. The method of claim 385, wherein the cancer comprises a benign or malignant carcinoma.
PCT/US2002/039509 2001-12-11 2002-12-10 Growth hormone releasing hormone suplementation for treating chronically ill subjects WO2003049700A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2002357143A AU2002357143B2 (en) 2001-12-11 2002-12-10 Growth hormone releasing hormone supplementation for treating chronically ill subjects
BR0214869-2A BR0214869A (en) 2001-12-11 2002-12-10 Plasmid-mediated supplementation for treatment of chronically ill individuals
MXPA04005713A MXPA04005713A (en) 2001-12-11 2002-12-10 Growth hormone releasing hormone suplementation for treating chronically ill subjects.
CA2469310A CA2469310C (en) 2001-12-11 2002-12-10 Plasmid mediated supplementation for treating chronically ill subjects
EP02804771.0A EP1465654B1 (en) 2001-12-11 2002-12-10 Plasmid mediated supplementation for treating chronically ill subjects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33961001P 2001-12-11 2001-12-11
US60/339,610 2001-12-11

Publications (3)

Publication Number Publication Date
WO2003049700A2 WO2003049700A2 (en) 2003-06-19
WO2003049700A3 WO2003049700A3 (en) 2003-09-18
WO2003049700B1 true WO2003049700B1 (en) 2003-10-30

Family

ID=23329825

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/039509 WO2003049700A2 (en) 2001-12-11 2002-12-10 Growth hormone releasing hormone suplementation for treating chronically ill subjects

Country Status (11)

Country Link
US (2) US7241744B2 (en)
EP (1) EP1465654B1 (en)
CN (1) CN1615151A (en)
AR (1) AR037778A1 (en)
AU (1) AU2002357143B2 (en)
BR (1) BR0214869A (en)
CA (1) CA2469310C (en)
MX (1) MXPA04005713A (en)
MY (1) MY142457A (en)
TW (1) TW200301778A (en)
WO (1) WO2003049700A2 (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1578901A4 (en) * 2001-09-07 2006-03-29 Baylor College Medicine Linear dna fragments for gene expression
ATE536100T1 (en) * 2001-10-26 2011-12-15 Baylor College Medicine COMPOSITION FOR ALTERING BONE PROPERTIES IN A SUBJECT
CN1615151A (en) * 2001-12-11 2005-05-11 阿德维希斯公司 Plasmid mediated suplementation for treating chronically ill subjects
ATE510919T1 (en) * 2002-02-07 2011-06-15 Baylor College Medicine ALTERED Pituitary Gland Development in Offspring of Pregnant Mothers Treated with Growth Hormone-Releasing Hormone Therapy
WO2003099341A1 (en) * 2002-05-28 2003-12-04 Advisys, Inc. Increased delivery of a nucleic acid constrtuct in vivo by the poly-l-glutamate (plg) system
EP1573004A4 (en) * 2002-11-04 2006-08-09 Advisys Inc Synthetic muscle promoters with activities exceeding naturally occurring regulatory sequences in cardiac cells
TW200424214A (en) * 2003-04-21 2004-11-16 Advisys Inc Plasmid mediated GHRH supplementation for renal failures
US7468273B2 (en) 2003-05-01 2008-12-23 Meial Limited Canine GHRH gene, polypeptides and methods of use
CA2575926C (en) * 2003-08-04 2014-02-25 Advisys, Inc. Canine specific growth hormone releasing hormone
US20060025368A1 (en) * 2004-07-23 2006-02-02 Advisys, Inc. Growth hormone releasing hormone enhances vaccination response
US7846720B2 (en) * 2005-01-26 2010-12-07 Vgx Pharmaceuticals, Inc. Optimized high yield synthetic plasmids
ES2343270T3 (en) 2005-04-25 2010-07-27 Merial Ltd. VACCINES AGAINST VIRUS NIPAH.
JP2009515529A (en) 2005-11-14 2009-04-16 メリアル リミテッド Gene therapy for renal failure
US7771995B2 (en) 2005-11-14 2010-08-10 Merial Limited Plasmid encoding human BMP-7
US8980249B2 (en) 2010-06-03 2015-03-17 University Of Miami Agonists of growth hormone releasing hormone as effectors for survival and proliferation of pancreatic islets
WO2012145577A1 (en) 2011-04-20 2012-10-26 Merial Limited Adjuvanted rabies vaccine with improved viscosity profile
US8993316B2 (en) 2011-11-16 2015-03-31 Brian P. Hanley Methods and compositions for gene therapy and GHRH therapy
US9079974B2 (en) * 2011-12-21 2015-07-14 The University Of Miami GH-RH analogs with potent agonistic effects
WO2013138776A1 (en) 2012-03-16 2013-09-19 Merial Limited Novel methods for providing long-term protective immunity against rabies in animals, based upon administration of replication-deficient flavivirus expressing rabies g
EP2934565B1 (en) 2012-12-21 2019-03-13 University of Miami Ghrh agonists for the treatment of ischemic disorders
EP2935317B1 (en) 2012-12-21 2019-03-27 University of Miami Ghrh agonists for islet cell transplantation and function and the treatment of diabetes

Family Cites Families (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4228156A (en) * 1979-03-30 1980-10-14 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4228158A (en) * 1979-03-30 1980-10-14 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4226857A (en) * 1979-03-30 1980-10-07 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4223019A (en) * 1979-03-30 1980-09-16 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4223020A (en) * 1979-03-30 1980-09-16 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4224316A (en) 1979-03-30 1980-09-23 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4223021A (en) * 1979-03-30 1980-09-16 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4410512A (en) 1981-12-28 1983-10-18 Beckman Instruments, Inc. Combinations having synergistic pituitary growth hormone releasing activity
NL8200523A (en) 1982-02-11 1983-09-01 Univ Leiden METHOD FOR TRANSFORMING IN VITRO PLANT PROTOPLASTS WITH PLASMIDE DNA.
US5134120A (en) 1984-08-03 1992-07-28 Cornell Research Foundation, Inc. Use of growth hormone to enhance porcine weight gain
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US5036045A (en) 1985-09-12 1991-07-30 The University Of Virginia Alumni Patents Foundation Method for increasing growth hormone secretion
US4833166A (en) 1987-05-01 1989-05-23 Grosvenor Clark E Growth hormone releasing hormone complementary peptides
US4839344A (en) 1987-06-12 1989-06-13 Eastman Kodak Company Polypeptide compounds having growth hormone releasing activity
USRE33699E (en) 1987-07-09 1991-09-24 International Minerals & Chemical Corp. Growth hormone-releasing factor analogs
FR2622455B1 (en) 1987-11-04 1991-07-12 Agronomique Inst Nat Rech APPLICATION OF THE HUMAN GROWTH HORMONE SECRETION STIMULATION FACTOR, ITS ACTIVE FRAGMENTS AND RELATED ANALOGS, TO INCREASE DAIRY PRODUCTION AND NEWBORN WEIGHT IN MAMMALS
US4952500A (en) 1988-02-01 1990-08-28 University Of Georgia Research Foundation, Inc. Cloning systems for Rhodococcus and related bacteria
US4956288A (en) * 1988-04-22 1990-09-11 Biogen, Inc. Method for producing cells containing stably integrated foreign DNA at a high copy number, the cells produced by this method, and the use of these cells to produce the polypeptides coded for by the foreign DNA
US5023322A (en) 1988-08-31 1991-06-11 Mta Kutatas-Es Szervezetelemzo Intezete Analogs of growth hormone releasing factor (GRF) and a method for the preparation thereof
US5084442A (en) * 1988-09-06 1992-01-28 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US5302523A (en) * 1989-06-21 1994-04-12 Zeneca Limited Transformation of plant cells
US5550318A (en) * 1990-04-17 1996-08-27 Dekalb Genetics Corporation Methods and compositions for the production of stably transformed, fertile monocot plants and cells thereof
US7705215B1 (en) 1990-04-17 2010-04-27 Dekalb Genetics Corporation Methods and compositions for the production of stably transformed, fertile monocot plants and cells thereof
US5137872A (en) 1989-09-18 1992-08-11 Pitman-Moore, Inc. Growth hormone-releasing factor analogs
US5322783A (en) 1989-10-17 1994-06-21 Pioneer Hi-Bred International, Inc. Soybean transformation by microparticle bombardment
US5484956A (en) 1990-01-22 1996-01-16 Dekalb Genetics Corporation Fertile transgenic Zea mays plant comprising heterologous DNA encoding Bacillus thuringiensis endotoxin
NZ238748A (en) * 1990-06-29 1993-09-27 Hoffmann La Roche Growth hormone releasing factor (grf) analogues
US5486505A (en) * 1990-07-24 1996-01-23 Polygen Holding Corporation Polypeptide compounds having growth hormone releasing activity
US5384253A (en) * 1990-12-28 1995-01-24 Dekalb Genetics Corporation Genetic transformation of maize cells by electroporation of cells pretreated with pectin degrading enzymes
JPH05507939A (en) * 1991-04-09 1993-11-11 エフ・ホフマン―ラ　ロシユ　アーゲー Analogs of growth hormone releasing factor
WO1993004169A1 (en) * 1991-08-20 1993-03-04 Genpharm International, Inc. Gene targeting in animal cells using isogenic dna constructs
US5663146A (en) * 1991-08-22 1997-09-02 Administrators Of The Tulane Educational Fund Polypeptide analogues having growth hormone releasing activity
US5610042A (en) * 1991-10-07 1997-03-11 Ciba-Geigy Corporation Methods for stable transformation of wheat
US5925564A (en) * 1991-11-06 1999-07-20 Baylor College Of Medicine Expression vector systems and method of use
US5298422A (en) * 1991-11-06 1994-03-29 Baylor College Of Medicine Myogenic vector systems
JP3368603B2 (en) * 1992-02-28 2003-01-20 オリンパス光学工業株式会社 Gene therapy treatment device
US6033884A (en) 1992-03-20 2000-03-07 Baylor College Of Medicine Nucleic acid transporter systems and methods of use
DE69333434T2 (en) 1992-04-03 2005-03-03 The Regents Of The University Of California, Oakland SELF-ORGANIZING SYSTEM FOR THE ADMINISTRATION OF POLYNUCLEOTIDES CONTAINING AN AMPHIPHATIC PEPTIDE
DE69334150T2 (en) * 1992-05-14 2008-03-13 Baylor College Of Medicine, Houston MUTATED STEROID HORMONE RECEPTORS, METHODS FOR THEIR USE, AND MOLECULAR SWITCHES FOR GENE THERAPY
DE69334225D1 (en) * 1992-07-07 2008-07-31 Japan Tobacco Inc METHOD FOR TRANSFORMING A MONOCOTYLEDONE PLANT
US5702932A (en) 1992-07-20 1997-12-30 University Of Florida Microinjection methods to transform arthropods with exogenous DNA
HUT70467A (en) * 1992-07-27 1995-10-30 Pioneer Hi Bred Int An improved method of agrobactenium-mediated transformation of cultvred soyhean cells
DE4228457A1 (en) 1992-08-27 1994-04-28 Beiersdorf Ag Production of heterodimeric PDGF-AB using a bicistronic vector system in mammalian cells
GB9222888D0 (en) 1992-10-30 1992-12-16 British Tech Group Tomography
US5439440A (en) * 1993-04-01 1995-08-08 Genetronics, Inc. Electroporation system with voltage control feedback for clinical applications
US5656610A (en) * 1994-06-21 1997-08-12 University Of Southern California Producing a protein in a mammal by injection of a DNA-sequence into the tongue
FR2722208B1 (en) 1994-07-05 1996-10-04 Inst Nat Sante Rech Med NEW INTERNAL RIBOSOME ENTRY SITE, VECTOR CONTAINING SAME AND THERAPEUTIC USE
US5736524A (en) 1994-11-14 1998-04-07 Merck & Co.,. Inc. Polynucleotide tuberculosis vaccine
US5792747A (en) 1995-01-24 1998-08-11 The Administrators Of The Tulane Educational Fund Highly potent agonists of growth hormone releasing hormone
JPH11503454A (en) 1995-04-14 1999-03-26 ジ アドミニストレイターズ オブ ザ チューレン エデュケイショナル ファンド Analogs of growth hormone releasing factor
US5780448A (en) 1995-11-07 1998-07-14 Ottawa Civic Hospital Loeb Research DNA-based vaccination of fish
US5928906A (en) 1996-05-09 1999-07-27 Sequenom, Inc. Process for direct sequencing during template amplification
US5945100A (en) 1996-07-31 1999-08-31 Fbp Corporation Tumor delivery vehicles
JP4320054B2 (en) * 1996-08-13 2009-08-26 ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド Compositions and methods for polynucleotide delivery
US5981274A (en) * 1996-09-18 1999-11-09 Tyrrell; D. Lorne J. Recombinant hepatitis virus vectors
US5704908A (en) * 1996-10-10 1998-01-06 Genetronics, Inc. Electroporation and iontophoresis catheter with porous balloon
US6423693B1 (en) * 1997-07-24 2002-07-23 Baylor College Of Medicine Growth hormone releasing hormone expression system and methods of use, including use in animals
US5994624A (en) * 1997-10-20 1999-11-30 Cotton Incorporated In planta method for the production of transgenic plants
US6194402B1 (en) * 1998-09-02 2001-02-27 Merck & Co., Inc. Enhancement of return to independent living status with a growth hormone secretagogue
BR0001606A (en) * 1999-04-12 2001-04-24 Pfizer Prod Inc Compositions of growth hormone and growth hormone releasing hormone
US6551996B1 (en) * 1999-07-26 2003-04-22 Baylor College Of Medicine Super-active porcine growth hormone releasing hormone analog
CN1615151A (en) * 2001-12-11 2005-05-11 阿德维希斯公司 Plasmid mediated suplementation for treating chronically ill subjects
CA2567741A1 (en) * 2004-05-25 2006-03-30 Chimeracore, Inc. Self-assembling nanoparticle drug delivery system
US9302725B2 (en) 2013-03-14 2016-04-05 Bell Sports, Inc. Locking rack system for bicycles
EP3146120A4 (en) 2014-05-19 2017-11-29 Felix L. Sorkin Modified permanent cap

Also Published As

Publication number Publication date
BR0214869A (en) 2005-03-08
US8178504B2 (en) 2012-05-15
AU2002357143A1 (en) 2003-06-23
WO2003049700A2 (en) 2003-06-19
MY142457A (en) 2010-11-30
EP1465654B1 (en) 2015-02-25
AU2002357143B2 (en) 2009-07-30
CA2469310A1 (en) 2003-06-19
EP1465654A2 (en) 2004-10-13
US20040057941A1 (en) 2004-03-25
AR037778A1 (en) 2004-12-01
US20090170748A1 (en) 2009-07-02
MXPA04005713A (en) 2005-06-06
WO2003049700A3 (en) 2003-09-18
US7241744B2 (en) 2007-07-10
CA2469310C (en) 2013-01-29
TW200301778A (en) 2003-07-16
CN1615151A (en) 2005-05-11
EP1465654A4 (en) 2007-08-29

Similar Documents

Publication Publication Date Title
WO2003049700B1 (en) Growth hormone releasing hormone suplementation for treating chronically ill subjects
Cemazar et al. Cancer electrogene therapy with interleukin-12
CA1306212C (en) Insulin analogues and process for their preparation
EP0963207B1 (en) IL12 for the gene therapy of tumours
EP1543020B1 (en) Codon optimized synthetic plasmids
WO2003038112B1 (en) A composition and method to alter lean body mass and bone properties in a subject
IL173158A (en) Polypeptide having an improved cytosine deaminase activity
CA2174863A1 (en) Translational enhancer dna
CA2178482A1 (en) Thrombopoietin
US6001816A (en) Gene therapy for leptin deficiency
KR102267837B1 (en) Recombinant vaccinia virus and pharmacecutical compositon comprising same
CA2252470A1 (en) Treatment of human cancers with an adenovirus vector containing an interferon consensus gene
EP1740702B1 (en) Canine ghrh gene, polypeptides and methods of use
CN108025090B (en) Composition for treating pain
DK1618197T3 (en) DOG GHRH GENES, POLYPEPTIDES AND METHODS OF USE
EP0921820A1 (en) Gene therapy for obesity
EP1458240A2 (en) Nucleic acid constructs useful for glucose regulated production of human insulin in somatic cell lines
EP1218508B1 (en) DNA sequences for the enhancement of feed efficiency and growth rate of pigs
EP1513559A1 (en) Increased delivery of a nucleic acid constrtuct in vivo by the poly-l-glutamate (plg) system
NZ510943A (en) Delivery system for porcine somatotropin
KR20100098634A (en) Increased stability of a dna formulation by including poly-l-glutamate
US20010010926A1 (en) New immunoregulatory protein lst-1
KR20030087582A (en) Antitumor Compositions Containing Expression Plasmids Having Mutated IL―12 Gene And Anti-angiogenetic Peptides
Tomasoni et al. The goal of intragraft gene therapy
Nagayama Gene therapy for thyroid cancer

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
B Later publication of amended claims

Free format text: 20030916

WWE Wipo information: entry into national phase

Ref document number: 2469310

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/005713

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2002357143

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2002804771

Country of ref document: EP

Ref document number: 534027

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2002827105X

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2002804771

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: JP