INHIBITOR OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA COACTIVATOR 1

• US 20090029933A1
• Filed: 03/20/2006
• Published: 01/29/2009
• Est. Priority Date: 03/23/2005
• Status: Abandoned Application

• Current Assignee: Universidade Estadual De Campinas - Unicamp.
• Original Assignee: Universidade Estadual De Campinas - Unicamp.
• Inventors: Velloso, Licio Augusto, de Souza, Claudio Teodoro
• Application Number:
  US11/909,323
• Publication Number:
  US 20090029933A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense

Abstract

The present invention refers to the use of an antisense DNA oligonucleotide for the messenger RNA of the PGC-1α protein, useful as drug for the treatment of diabetes mellitus, insulin resistance and metabolic syndrome. More specifically, the present invention deals with a compound used as drug, through enteral or parenteral route, preferably, with the property of inhibiting the protein expression peroxisome proliferator-activated receptor alpha Coactivator 1 (PGC-1α) leading to the reduction of the blood glucose levels. It deals, therefore, with a pharmacological compound that promotes, in diabetic and insulin-resistant individuals, improvement of the glucose serum levels, increase of the plasmatic insulin concentration and reduction of insulin resistance. The present invention presents a more effective control of the glucose levels and acts beneficially on other complications associated to the Diabetes and obesity conditions, according to tests performed in animal models. In this manner, the principal advantage of the present invention over others alike already existing in the market is the effectiveness that controls blood glucose levels and the fact of acting beneficially on other complications that accompany the disease.

Claims

1. ) An OLIGONUCLEOTIDE consisting of 80 synthetic or natural bases corresponding to the following modified or unmodified sequences:

i. Sequence no. 1 (SEQ ID NO;

1), 5′

-tggagttgaa aaagcttgac tggcgtcatt caggagctgg atggcgtggg acatgtgcaa ccaggactct gagtctgtat-3′

;

ii. Sequence no. 2 (SEQ ID NO;

2), 5′

-tgctctgtgt cactgtggat tggagttgaa aaagcttgac tggcgtcatt caggagctgg atggcgtggg acatgtgcaa-3′

;

iii. Sequence no. 3 (SEQ ID NO;

3), 5′

-tggcgtcatt caggagctgg atggcgtggg acatgtgcaa ccaggactct gagtctgtat ggagtgacat cgagtgtgct-3′

; and

iv. a fragment of Sequence no. 1 (SEQ ID NO;

1), Sequence no. 2 (SEQ ID NO;

2), or Sequence no. 3 (SEQ ID NO;

3), that has at least 5 bases.

2. ) The OLIGONUCLEOTIDE, according to claim 1, wherein the sequence includes the bases of any of the Sequence no. 1 (SEQ ID NO:

1), Sequence no. 2 (SEQ ID NO;

2), and Sequence no. 3 (SEQ ID NO;

3) in the positions from the group consisting of from 1 to 20, from 2 to 21, from 3 to 22, from 4 to 23, from 5 to 24, from 6 to 25, from 7 to 26, from 8 to 27, from 9 to 28, from 10 to 29, from 11 to 30, from 12 to 31, from 13 to 32, from 14 to 33, from 15 to 34, from 16 to 35, from 17 to 36, from 18 to 37, from 19 to 38, from 20 to 39, from 21 to 40, from 22 to 41, from 23 to 42, from 24 to 43, from 25 to 44, from 26 to 45, from 27 to 46, from 28 to 47, from 29 to 48, from 30 to 49, from 31 to 50, from 32 to 51, from 33 to 52, from 34 to 53, from 35 to 54, from 36 to 55, from 37 to 56, from 38 to 57, from 39 to 58, from 40 to 59, from 41 to 60, from 42 to 61, from 43 to 62, from 44 to 63, from 45 to 64, from 46 to 65, from 47 to 66, from 48 to 67, from 49 to 68, from 50 to 69, from 51 to 70, from 52 to 71, from 53 to 72, from 54 to 73, from 55 to 74, from 56 to 75, from 57 to 76, from 58 to 77, from 59 to 78, from 60 to 79, and from 61 to 80.

63. ) The OLIGONUCLEOTIDE, according to claim 1, wherein the sequence includes the bases of any of the Sequence no. 1 (SEQ ID NO:

1), Sequence no. 2 (SEQ ID NO;

2), or Sequence no. 3 (SEQ ID NO;

3) in the position from the group consisting of from 26 to 41, from 27 to 42, from 28 to 43, from 29 to 44, from 30 to 45, from 31 to 46, and from 32 to 47.

70. ) The OLIGONUCLEOTIDE according to claim 1, further comprising at least one fragment varying between 5 to 79 bases that is contained in the Sequence no. 1 (SEQ ID NO:

1), Sequence no. 2 (SEQ ID NO;

2), or Sequence no. 3 (SEQ ID NO;

3).

71. ) A PHARMACEUTICAL COMPOUND for the manufacture of a medication wherein the compound comprises an oligonucleotide according to claims 1, 2, 63 or 70.

72. ) The PHARMACEUTICAL COMPOUND, according to claim 71, wherein the medication administration route is enteral.

73. ) A method of treating diabetes mellitus, insulin resistance, and/or metabolic syndrome comprising the step of administering to an individual with diabetes mellitus, insulin resistance, and/or metabolic syndrome THE PHARMACEUTICAL COMPOUND of claim 71.

74. ) The PHARMACEUTICAL COMPOUND of claim 71 in a pharmaceutically effective quantity, having a pharmaceutically effective quantity of the oligonucleotide, and further comprising at least one of a pharmaceutically effective quantity of vehicles, diluents, solvents and excipients, pharmaceutically acceptable for therapeutic application.

75. ) The PHARMACEUTICAL COMPOUND according to claim 71 or 74

wherein the medication is for the treatment of diabetes mellitus, insulin resistance and metabolic syndrome.

76. ) The PHARMACEUTICAL COMPOUND according to claim 74 wherein the pharmaceutically effective quantity of the compound is from about 200 nMol to about 2000 nMol per dose.

78. ) A method of treating diabetes mellitus comprising the step of administering to a individual with diabetes mellitus THE PHARMACEUTICAL COMPOUND of claim 74.

79. ) An EXPRESSION VECTOR for the manufacture of medications for the treatment of diabetes mellitus, insulin resistance and metabolic syndrome wherein the vector comprises a sequence corresponding to the oligonucleotide of claims 1, 2, 63, or 70 and wherein the vector is capable of transforming a host cell in a bioreactor of the compound of claims 71 or 72.

80. ) The pharmaceutical compound of claim 71 wherein the oligonucleotide is modified.

81. ) The pharmaceutical compound of claim 71 wherein the oligonucleotide is unmodified.

82. ) The pharmaceutical compound of claim 71 wherein the oligonucleotide is synthetic.

83. ) The pharmaceutical compound of claim 71 wherein the oligonucleotide is natural.

84. ) The pharmaceutical compound of claim 71 wherein the medication administration route is parenteral.

85. ) A method of treating insulin resistance comprising the step of administering to an individual with insulin resistance the pharmaceutical compound of claim 74.

86. ) A method of treating metabolic syndrome comprising the step of administering to an individual with metabolic syndrome the pharmaceutical compound of claim 74.

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