BIOMARKERS OF SIRTUIN ACTIVITY AND METHODS OF USE THEREOF

• US 20100215632A1
• Filed: 03/19/2008
• Published: 08/26/2010
• Est. Priority Date: 03/19/2007
• Status: Abandoned Application

• Current Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GSK plc)
• Inventors: Smith, Jesse, Iffland, Andre, Boss, Olivier, Worcester, Siva, Jirousek, Michael, Milne, Jill
• Application Number:
  US12/450,252
• Publication Number:
  US 20100215632A1
• Time in Patent Office: Days
• US Class Current: 424/94.100
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12Q 1/34 involving hydrolase
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

Provided are methods for monitoring sirtuin modulation in a subject, for example, during therapeutic treatment with a sirtuin modulating compound. The methods involve determining the expression level of one or more sirtuin biomarkers in a biological sample from the subject. Also provided are methods for identifying compounds that modulate the activity of a sirtuin protein using one or more sirtuin biomarkers.

Claims

1. A method of detecting sirtuin modulation in a subject comprising determining the expression level of at least one sirtuin biomarker in a biological sample from the subject, wherein a change in the expression level of the sirtuin biomarker as compared to a control is indicative of sirtuin modulation.

3. The method of claim 1, wherein the subject is suffering from a disease or disorder related to aging or stress, diabetes, obesity, a neurodegenerative disease, chemotherapeutic induced neuropathy, neuropathy associated with an ischemic event, an ocular disease or disorder, cardiovascular disease, a blood clotting disorder, inflammation, or flushing.

7. The method of claim 1, wherein the sirtuin biomarker is at least one of the following:

MCP-1, BMP Receptor 1A, Smpd13a, CD14, ApoE, FAS, Transthyretin, FABP1, Acyl-CoA thioesterase 1, Acyl-CoA thioesterase 2, Aquaporin 4, Rrad, CXCL9, CCL8, Ppp1r3g, ApoA-I, ApoA-II, or ApoB.

8. The method of claim 7, wherein the sirtuin biomarker is MCP-1.

9. The method of claim 1, wherein the expression level of a sirtuin biomarker is determined by measuring the mRNA level of the sirtuin biomarker, the protein level of the sirtuin biomarker, or the activity of the sirtuin biomarker.

13. The method of claim 8, wherein a decrease in the expression level of MCP-1 as compared to a control is indicative of sirtuin activation.

2. (canceled)

4-6. -6. (canceled)

10-12. -12. (canceled)

14-17. -17. (canceled)

18. A method for monitoring therapeutic treatment with a sirtuin modulator comprising determining the expression level of at least one sirtuin biomarker in a biological sample from a subject being treated with a sirtuin modulator.

19-36. -36. (canceled)

37. A method for monitoring the progress of therapeutic treatment with a sirtuin modulator, comprising:

a) administering a sirtuin modulator to a subject,

b) obtaining a biological sample from said subject, and

c) determining the expression level of at least one sirtuin biomarker in the biological sample;

wherein an altered expression level of the sirtuin biomarker in the biological sample as compared to a control is indicative of therapeutic sirtuin modulation in said subject.

38-42. -42. (canceled)

43. A method for identifying a subject that would benefit from treatment with a sirtuin modulating compound, comprising determining the expression level of at least one sirtuin biomarker in a biological sample from the subject, wherein an altered expression level of the sirtuin biomarker as compared to a control is indicative of a subject that would benefit from treatment with a sirtuin modulating compound.

44-48. -48. (canceled)

49. A method for evaluating a subject'"'"'s risk of developing a sirtuin-mediated disease or disorder, comprising determining the expression level of at least one sirtuin biomarker in a biological sample from the subject, wherein an altered expression level of the sirtuin biomarker as compared to a control is indicative of a subject at risk for developing a sirtuin-mediated disease or disorder.

50-52. -52. (canceled)

53. A method for identifying a compound that modulates sirtuin activity, comprising:

a) contacting a cell expressing a sirtuin protein with a test compound, and

b) determining the expression level of at least one sirtuin biomarker in the cell, wherein a change in the expression level of the sirtuin biomarker in the presence of the test compound as compared to a control is indicative of a compound that modulates sirtuin activity.

54-56. -56. (canceled)

57. A method for treating a sirtuin-mediated disease or disorder in a subject, comprising:

a) administering a sirtuin modulating compound to the subject, and

b) monitoring the expression level of at least one sirtuin biomarker over time to determine whether the course of treatment in the subject should be modified.

58-61. -61. (canceled)

62. A kit for detecting the expression level of a sirtuin biomarker, comprising at least one component for determining the expression level of a sirtuin biomarker and at least one sirtuin modulating compound.

63. The kit of claim 62, wherein the component for determining the expression level of a sirtuin biomarker is at least one of the following:

an antibody or an antigen-binding fragment thereof that binds to the sirtuin biomarker, a set of PCR primers that specifically amplify the sirtuin biomarker mRNA, or a solid support comprising at least a fragment of the polynucleotide sequence encoding the sirtuin biomarker attached thereto.

64. The kit of claim 62, further comprising one or more of the following:

a detection label, buffer, or instructions for use.

65. The kit of claim 62, further comprising a cell line that expresses a sirtuin protein.

66. A method of determining the level of sirtuin activity in a biological sample comprising determining the expression level of at least one sirtuin biomarker in the biological sample.

67. A method of detecting sirtuin modulation in a subject comprising determining the expression level of FGF21 in a biological sample from the subject, wherein a change in the expression level of FGF21 as compared to a control is indicative of sirtuin modulation.

68. A method for monitoring therapeutic treatment with a sirtuin modulator comprising determining the expression level of FGF21 in a biological sample from a subject being treated with a sirtuin modulator, wherein a change in the expression level of FGF21 upon treatment with the sirtuin modulator is indicative of therapeutic sirtuin modulation in the subject.

69. A method for monitoring the progress of therapeutic treatment with a sirtuin modulator, comprising:

a) administering a sirtuin modulator to a subject,

b) obtaining a biological sample from said subject, and

c) determining the expression level of FGF21 in the biological sample;

wherein an altered expression level of FGF21 in the biological sample as compared to a control is indicative of therapeutic sirtuin modulation in said subject.

70. A method for identifying a subject that would benefit from treatment with a sirtuin modulating compound, comprising determining the expression level of FGF21 in a biological sample from the subject, wherein an altered expression level of FGF21 as compared to a control is indicative of a subject that would benefit from treatment with a sirtuin modulating compound.

71. A method for evaluating a subject'"'"'s risk of developing a sirtuin-mediated disease or disorder, comprising determining the expression level of FGF21 in a biological sample from the subject, wherein an altered expression level of FGF21 as compared to a control is indicative of a subject at risk for developing a sirtuin-mediated disease or disorder.

72. A method for identifying a compound that modulates sirtuin activity, comprising:

a) contacting a cell expressing a sirtuin protein with a test compound, and

b) determining the expression level of FGF21 in the cell, wherein a change in the expression level of FGF21 in the presence of the test compound as compared to a control is indicative of a compound that modulates sirtuin activity.

73. A method for treating a sirtuin-mediated disease or disorder in a subject, comprising:

a) administering a sirtuin modulating compound to the subject, and

b) monitoring the expression level of FGF21 over time to determine whether the course of treatment in the subject should be modified.

74-86. -86. (canceled)