Molecular signatures to predict long-term liver fibrosis progression
AssigneesBoard of Regents, The University of Texas System, Universite De Strasbourg, Inserm (Institut National De La Sante Et De La Recherche Medicale), HôPitaux Universitaires De Strasbourg (Hus)
InventorsYujin HOSHIDA, Naoto FUJIWARA, Amit SINGAL, Thomas Fredy BAUMERT
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Abstract
Disclosures herein are directed to methods and compositions for predicting high- and low-risk for liver fibrosis progression in patients. Based on the results achieved from the methods and compositions disclosed herein, liver disease patients can be classified into a prognostic risk group, which enables early diagnosis and prevention of liver fibrosis and other lethal complications. Methods and compositions disclosed herein substantially improve the poor prognosis of subjects having or at risk for one or more liver fibrosis.
Claims49
A method of predicting risk for liver fibrosis progression in a subject comprising determining a fibrosis progression signature (FPSec) score for the subject, wherein the subject is having or is suspected of having a disease, a condition, or any combination thereof that predisposes the subject to liver fibrosis.
A method of determining a fibrosis progression signature (FPSec) score for a subject comprising:
- (a) obtaining a sample of blood from the subject;
- (b) subjecting the sample to a multi-analyte profiling assay for protein quantification of one or more proteins, wherein the proteins comprise angiogenin, matrix metallopeptidase 7 (MMP-7), insulin like growth factor binding protein 7 (IGFBP-7), protein S (PROS1), vascular cell adhesion molecule 1 (VCAM-1), interleukin 6 (IL-6) C-C motif chemokine ligand 21 (CCL-21) or any combination thereof, to obtain a protein quantification measurement for each of the one or more proteins;
- (c) normalizing the protein quantification measurements of angiogenin, MMP-7, IGFBP-7, protein S, VCAM-1, IL-6, and/or CCL-21 to median fluorescent intensity to obtain a normalized protein quantification measurement for each of the one or more proteins;
- and
- (d) converting the normalized protein quantification measurements of angiogenin, MMP-7, IGFBP-7, protein S, VCAM-1, IL-6, and/or CCL-21 into an aggregated score, wherein the aggregated score is the FPSec score.
A diagnostic kit for determining a fibrosis progression signature (FPSec) score of a subject comprising one or more reagents for use in a multi-analyte profiling assay.
A method of treating liver fibrosis in a subject at high risk for liver fibrosis progression, the method comprising:
- (a) determining if the subject is at high risk for liver fibrosis progression by:
- (i) obtaining a sample of blood from the subject;
- (ii) determining protein levels of at least two liver disease biomarkers in the sample wherein,
- one of the at least two liver disease biomarkers is selected from vascular cell adhesion molecule 1 (VCAM-1), insulin-like growth factor-binding protein 7 (IGFBP-7), matrix metallopeptidase 7 (MMP-7), interleukin-6 (IL-6), and C-C motif chemokine ligand 21 (CCL-21);
- and
- the other one of the at least two liver disease biomarkers is selected from angiogenin and protein S;
- (iii) determining that the subject is at high risk for liver fibrosis progression if the one of the at least two liver disease biomarkers selected from VCAM-1, IGFBP-7, MMP-7, IL-6, and CCL-21 has a higher protein expression compared to a control, and the other one of the at least two liver disease biomarkers selected from angiogenin and protein S has a lower protein expression compared to a control,
- wherein the control is a sample of blood from a subject known to not have any liver disease;
- and
- (b) administering one or more treatments of liver fibrosis to the subject determined to be at high risk for liver fibrosis progression.
A method of predicting risk for liver fibrosis progression in a subject comprising determining a fibrosis progression signature (FPS) score for the subject, wherein the subject is having or is suspected of having a disease, a condition, or a combination thereof that predisposes the subject to liver fibrosis.
A method of determining a fibrosis progression signature (FPS) score for a subject comprising:
- (a) obtaining a liver biopsy sample from the subject;
- (b) subjecting the sample to a multi-analyte profiling assay for gene expression of one or more genes, wherein the genes comprise ANXA1, AEBP1, FBN1, IER3, CCL21, CXCR4, KRT7, IGFBP6, FILIP1L LOXL2, BCL2, SLC71, DDR1, NTS, PMM1, NAAA, TTR, PON3, HAAO, F9, or any combination thereof, to obtain a gene expression measurement for each of the one or more genes;
- (c) normalizing the gene expression measurements of ANXA1, AEBP1, FBN1, IER3, CCL21, CXCR4, KRT7, IGFBP6, FILIP1L LOXL2, BCL2, SLC71, DDR1, NTS, PMM1, NAAA, TTR, PON3, HAAO, and/or F9 to expression levels of a control set of genes to obtain a gene expression profile of the subject;
- and
- (d) converting the gene expression profile of the subject into an FPS score, wherein the FPS score is a numerical value corresponding to a similarity between the gene expression profile of the subject and a high-risk reference gene expression profile or a low-risk reference gene expression profile.
A diagnostic kit for determining a fibrosis progression signature (FPS) score of a subject comprising one or more reagents for use in a multi-analyte profiling assay.
A method of treating liver fibrosis in a subject at high risk for liver fibrosis progression, the method comprising:
- (a) determining if the subject is at high risk for liver fibrosis progression by
- (i) obtaining a liver biopsy sample from the subject;
- (ii) subjecting the liver biopsy sample to a multi-analyte profiling assay for gene expression of one or more genes, wherein the genes comprise ANXA1, AEBP1, FBN1, IER3, CCL21, CXCR4, KRT7, IGFBP6, FILIP1L LOXL2, BCL2, SLC71, DDR1, NTS, PMM1, NAAA, TTR, PON3, HAAO, and/or F9 to obtain a gene expression measurement of each of the one or more genes;
- (iii) normalizing the gene expression measurements of ANXA1, AEBP1, FBN1, IER3, CCL21, CXCR4, KRT7, IGFBP6, FILIP1L LOXL2, BCL2, SLC71, DDR1, NTS, PMM1, NAAA, TTR, PON3, HAAO, and/or F9 to expression levels of a control set of genes to obtain a gene expression profile of the subject;
- (iv) converting the gene expression profile of the subject into an FPS score, wherein the FPS score is a numerical value corresponding to a similarity between the gene expression profile of the subject and a high-risk reference gene expression profile or a low-risk reference gene expression profile;
- and
- (v) determining that the subject is at high risk for liver fibrosis progression if the FPS score is greater than +1.3013, and
- (b) administering one or more treatments of liver fibrosis to the subject determined to be at high risk for developing liver fibrosis.
Dependencies are inferred from the claim text.