Therapeutic methods for reducing fat deposition and treating associated conditions

• US 20050014158A1
• Filed: 06/27/2003
• Published: 01/20/2005
• Est. Priority Date: 06/27/2002
• Status: Abandoned Application

• Current Assignee: Harkness Pharmaceuticals, Inc.
• Original Assignee: Harkness Pharmaceuticals, Inc.
• Inventors: Adam, Gail Isabel Reid, Dennis, Edward A., Cantor, Charles, Rubin, Byron, Denissenko, Mikhail F., Langdown, Maria L.
• Application Number:
  US10/607,806
• Publication Number:
  US 20050014158A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: G01N 2500/20 : cell-free systems
• CPC Class Codes: G01N 2800/042 : Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 33/564 : for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
• CPC Class Codes: G01N 33/566 : using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere

Abstract

Provided herein are methods for prognosing and diagnosing fat deposition and related disorders (e.g., obesity and non-insulin diabetes dependent mellitus (NIDDM)) in a subject, reagents and kits for carrying out the methods, methods for identifying candidate therapeutics for reducing fat deposition and related disorders, and therapeutic methods for reducing fat deposition or treating fat deposition related disorders in a subject. These embodiments are based in part upon an analysis of polymorphic variations of the nucleic acid set forth in SEQ ID NO:1.

Claims

1. A method for identifying a candidate therapeutic for fat reduction, which comprises:

(a) introducing a test molecule to a system which comprises a nucleic acid comprising a PLA2G1B nucleotide sequence selected from the group consisting of;

(i) the nucleotide sequence of SEQ ID NO;

1;

(ii) a nucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(iii) a nucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(iv) a fragment of a nucleotide sequence of (i), (ii), or (iii);

or

introducing a test molecule to a system which comprises a protein encoded by a nucleotide sequence of (i), (ii), (iii), or (iv); and

(b) determining the presence or absence of an interaction between the test molecule and the nucleic acid or protein,

whereby the presence of an interaction between the test molecule and the nucleic acid or protein identifies the test molecule as a candidate therapeutic for fat reduction.

2. The method of claim 1, wherein the system is an animal.

3. The method of claim 1, wherein the system is a cell.

4. The method of claim 1, wherein the PLA2G1B nucleotide sequence comprises a guanine at position 7328, a thymine at position 9182, or a guanine at position 7328 and a thymine at position 9182.

5. A method for reducing fat deposition in a subject, which comprises administering a candidate therapeutic of claim 1 to a subject in need thereof, whereby the candidate therapeutic reduces fat deposition in the subject.

6. A method for reducing fat deposition in a subject, which comprises contacting a PLA2G1B nucleic acid with one or more cells of a subject in need thereof, wherein the PLA2G1B nucleic acid comprises a nucleotide sequence selected from the group consisting of:

(a) the nucleotide sequence of SEQ ID NO;

1;

(b) a nucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a nucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a nucleotide sequence of (a), (b), or (c);

whereby contacting the one or more cells of the subject with the PLA2G1B nucleic acid reduces fat deposition.

7. A method for reducing fat deposition in a subject, which comprises contacting a PLA2G1B protein with one or more cells of a subject in need thereof, wherein the PLA2G1B protein is encoded by a PLA2G1B nucleotide sequence which comprises a polynucleotide sequence selected from the group consisting of:

(a) the polynucleotide sequence of SEQ ID NO;

1;

(b) a polynucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a polynucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a polynucleotide sequence of (a), (b), or (c);

whereby contacting the one or more cells of the subject with the PLA2G1B protein reduces fat deposition.

8. A method for reducing fat deposition in a subject, which comprises:

detecting the presence or absence of a polymorphic variant associated with fat deposition in a PLA2G1B nucleotide sequence in a nucleic acid sample from a subject, wherein the PLA2G1B nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of;

(a) the polynucleotide sequence of SEQ ID NO;

1;

(b) a polynucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a polynucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a polynucleotide sequence of (a), (b), or (c); and

administering a treatment that reduces fat deposition to a subject from whom the sample originated where the presence of a polymorphic variation associated with fat reduction is detected in the PLA2G1B nucleotide sequence.

9. The method of claim 8, wherein the polymorphic variant is a guanine at position 7328, a thymine at position 9182, or a guanine at position 7328 and a thymine at position 9182.

10. The method of claim 8, wherein the treatment is one or more selected from the group consisting of an appetite suppressant, a lipase inhibitor, a phospholipase inhibitor, an exercise regimen, a dietary regimen, psychological consoling, psychotherapy, and a psychotherapeutic.

11. A method for reducing fat deposition in a subject, which comprises administering to a subject a molecule that inhibits a PLA2G1B polypeptide in the digestive tract of the subject, whereby inhibition of the PLA2G1B polypeptide in the digestive tract of the subject reduces fat deposition in the subject.

12. A method for reducing fat deposition in a subject, which comprises administering to a subject a molecule that inhibits a PLA2G1B polypeptide, wherein the subject does not experience significant steatorrhea after the molecule is administered, whereby inhibition of the PLA2G1B polypeptide reduces fat deposition in the subject.

13. A method for reducing fat deposition in a subject, which comprises administering to a subject a molecule that inhibits a PLA2G1B polypeptide, wherein the molecule induces less steatorrhea in subjects as compared to steatorrhea caused in subjects by a lipase inhibitor, whereby inhibition of the PLA2G1B polypeptide reduces fat deposition in the subject.

14. A method for identifying a candidate therapeutic for alleviating NIDDM, which comprises:

(a) introducing a test molecule to a system which comprises a nucleic acid comprising a PLA2G1B nucleotide sequence selected from the group consisting of;

(i) the nucleotide sequence of SEQ ID NO;

1;

(ii) a nucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(iii) a nucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(iv) a fragment of a nucleotide sequence of (i), (ii), or (iii);

or

introducing a test molecule to a system which comprises a protein encoded by a nucleotide sequence of (i), (ii), (iii), or (iv); and

(b) determining the presence or absence of an interaction between the test molecule and the nucleic acid or protein,

whereby the presence of an interaction between the test molecule and the nucleic acid or protein identifies the test molecule as a candidate therapeutic for treating NIDDM.

15. The method of claim 14, wherein the system is an animal.

16. The method of claim 14, wherein the system is a cell.

17. The method of claim 14, wherein the PLA2G1B nucleotide sequence comprises a cytosine at position 7256 of SEQ ID NO:

1.

18. A method for treating NIDDM in a subject, which comprises administering a candidate therapeutic of claim 14 to the subject in need thereof, whereby the candidate therapeutic treats NIDDM in the subject.

19. A method for alleviating NIDDM in a subject, which comprises contacting a PLA2G1B nucleic acid with one or more cells of a subject in need thereof, wherein the PLA2G1B nucleic acid comprises a nucleotide sequence selected from the group consisting of:

(a) the nucleotide sequence of SEQ ID NO;

1;

(b) a nucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a nucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a nucleotide sequence of (a), (b), or (c);

whereby contacting the one or more cells of the subject with the PLA2G1B nucleic acid alleviates NIDDM.

20. A method for alleviating NIDDM in a subject, which comprises contacting a PLA2G1B protein with one or more cells of a subject in need thereof, wherein the PLA2G1B protein is encoded by a PLA2G1B nucleotide sequence which comprises a polynucleotide sequence selected from the group consisting of:

(a) the polynucleotide sequence of SEQ ID NO;

1;

(b) a polynucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a polynucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a polynucleotide sequence of (a), (b), or (c);

whereby contacting the one or more cells of the subject with the PLA2G1B protein alleviates NIDDM.

21. A method for alleviating NIDDM in a subject, which comprises:

detecting the presence or absence of a polymorphic variant associated with NIDDM in a PLA2G1B nucleotide sequence in a nucleic acid sample from a subject, wherein the PLA2G1B nucleotide sequence comprises a polynucleotide sequence selected from the group consisting of;

(a) the polynucleotide sequence of SEQ ID NO;

1;

(b) a polynucleotide sequence which encodes a polypeptide consisting of the amino acid sequence of SEQ ID NO;

2;

(c) a polynucleotide sequence which encodes a polypeptide that is 90% identical to the amino acid sequence of SEQ ID NO;

2; and

(d) a fragment of a polynucleotide sequence of (a), (b), or (c); and

administering a treatment that alleviates NIDDM to a subject from whom the sample originated where the presence of a polymorphic variation associated with NIDDM is detected in the PLA2G1B nucleotide sequence.

22. The method of claim 21, wherein the polymorphic variant is a cytosine at position 7256 of SEQ ID NO:

1.

23. The method of claim 21, wherein the treatment is one or more selected from the group consisting of insulin, a hypoglycemic, a starch blocker, a liver glucose regulating agent, an insulin sensitizer, a glucose level monitoring regimen, dietary counseling, and a dietary regimen for managing blood glucose levels.