Methods and Kits for Predicting Liver Fibrosis Progression Rate in Chronic Hepatitis C Patients

• US 20080299094A1
• Filed: 06/30/2005
• Published: 12/04/2008
• Est. Priority Date: 07/01/2004
• Status: Abandoned Application

• Current Assignee: Medical Research Fund of -Tel Aviv Sourasky Medical Center
• Original Assignee: Medical Research Fund of Tel Aviv
• Inventors: Oren, Ran
• Application Number:
  US11/631,340
• Publication Number:
  US 20080299094A1
• Time in Patent Office: Days
• US Class Current: 424/93.21
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/172 Haplotypes

Abstract

Methods and kits for determining predisposition of an individual to develop fast progression rate of liver fibrosis are provided. Also provided are agents and pharmaceutical compositions useful in preventing fast progression of liver fibrosis and a method of identifying drug molecules which accelerate or induce liver fibrosis.

Claims

1-49. -49. (canceled)

50. A method of determining if an individual is predisposed to fast progression of liver fibrosis, the method comprising determining a presence or absence, in a homozygous or heterozygous form, of at least one fast progression liver fibrosis-associated genotype in the CYP2D6 locus or in neighboring loci of the individual, said neighboring loci being in linkage disequilibrium with said CYP2D6 locus, thereby determining if the individual is predisposed to fast progression of liver fibrosis.

51. The method of claim 50, wherein the individual is infected with an hepatitis C virus.

52. The method of claim 50, wherein said at least one fast progression liver fibrosis-associated genotype in the CYP2D6 locus is an adenosine nucleotide-containing allele of the CYP2D6*4 SNP as set forth in SEQ ID NO:

1.

53. The method of claim 50, wherein said at least one fast progression liver fibrosis-associated genotype encodes a truncated CYP2D6 polypeptide.

54. The method of claim 51, wherein said presence of said genotype is indicative of increased predisposition risk of developing fast progression of liver fibrosis in the individual.

55. The method of claim 51, wherein said presence of said genotype is indicative of increased predisposition risk of developing liver cirrhosis.

56. A kit for determining if an individual is predisposed to fast progression of liver fibrosis, the kit comprising at least one reagent for determining a presence or absence in a homozygous or heterozygous form, of at least one fast progression liver fibrosis-associated genotype in the CYP2D6 locus or in neighboring loci of the individual, said neighboring loci are in linkage disequilibrium with said CYP2D6 locus.

57. A method of preventing fast progression of liver fibrosis in an individual in need thereof, the method comprising administering to the individual an agent capable of upregulating the expression level and/or activity of CYP2D6 in the liver of the individual, thereby preventing fast progression of liver fibrosis in the individual.

58. The method of claim 57, wherein said individual is infected with an hepatitis C virus.

59. The method of claim 57, wherein said individual is suffering from a disease selected from the group of an hepatitis viral infection, an hepatotoxicity, a liver cancer, a non alcoholic fatty liver disease (NAFLD), an autoimmune disease, a metabolic liver disease, and a disease with secondary involvement of the liver.

60. The method of claim 57, wherein said upregulating is effected by at least one approach selected from the group consisting of:

(a) expressing in liver cells of the individual an exogenous polynucleotide encoding at least a functional portion of CYP2D6;

(b) increasing expression of endogenous CYP2D6 in liver cells of the individual;

(c) increasing endogenous CYP2D6 activity in liver cells of the individual; and

(d) administering CYP2D6-expressing cells into the liver of the individual.

61. The method of claim 60, wherein said CYP2D6 is a polypeptide at least 75% identical to the polypeptide set forth by SEQ ID NO:

4 as determined using the BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters.

62. The method of claim 60, wherein said CYP2D6 is set forth by SEQ ID NO:

4.

63. The method of claim 60, wherein said polynucleotide is set forth by SEQ ID NO:

5.

64. A method of determining if a drug molecule is capable of inducing or accelerating development of fast progression of liver fibrosis in an individual, comprising comparing a metabolism rate of the drug molecule by a CYP2D6 and a poor metabolizing variant of said CYP2D6, wherein poor metabolism of the drug molecule by said poor metabolizing variant of said CYP2D6 and not said CYP2D6 is indicative of its capability of inducing or accelerating development of fast progression of liver fibrosis in the individual.

65. A method of determining if an individual is predisposed to fast progression of liver fibrosis, the method comprising determining a presence or absence, in a homozygous or heterozygous form, of at least one fast progression liver fibrosis-associated genotype in a locus selected from the group consisting of CYP3A5, CYP2E1 and APO E or in neighboring loci of the individual, said neighboring loci being in linkage disequilibrium with said locus, thereby determining if the individual is predisposed to fast progression of liver fibrosis.

67. The method of claim 65, wherein said at least one fast progression liver fibrosis-associated genotype in said CYP3A5 locus is an adenosine nucleotide-containing allele at nucleotide coordinate 174 of SEQ ID NO:

18.

68. The method of claim 65, wherein said at least one fast progression liver fibrosis-associated genotype in said CYP2E1 locus is a thymidine nucleotide-containing allele at nucleotide coordinate 1772 of SEQ ID NO:

17.

69. The method of claim 65, wherein said at least one fast progression liver fibrosis-associated genotype in said APO E locus is a cytosine nucleotide-containing allele at nucleotide coordinate 55 of SEQ ID NO:

19.

66. A kit for determining if an individual is predisposed to fast progression of liver fibrosis, the kit comprising at least one reagent for determining a presence or absence in a homozygous or heterozygous form, of at least one fast progression liver fibrosis-associated genotype in a locus selected from the group consisting of CYP3A5, CYP2E1 and APO E or in neighboring loci of the individual, said neighboring loci are in linkage disequilibrium with said locus.