Articles for diagnosis of liver fibrosis
Inventors
ABDULHAMEED, Mohamed Diwan M. • TAWA, Gregory J. • IPPOLITO, Danielle L. • Lewis, John A. • Wallqvist, Sven Anders • STALLINGS, Jonathan D. • PERMENTER, Matthew G.
Assignees
United States Department of the Army
Publication Number
US-11371097-B2
Publication Date
2022-06-28
Expiration Date
2036-01-29
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Abstract
Disclosed are methods and articles (e.g., gene arrays or antibodies) for determining the progression or regression of liver fibrosis, for the diagnosis of liver disease, and for screening compounds for hepatotoxicity and efficacy against liver fibrosis. Related therapeutic methods also are disclosed.
Core Innovation
Disclosed are methods and articles, such as gene arrays and antibodies, for determining the progression or regression of liver fibrosis and for diagnosing liver disease. The inventions also provide methods for screening compounds for hepatotoxicity and efficacy against liver fibrosis. The disclosed approaches enable detection of differential expression of at least twenty-five genes listed in Table 4 or their orthologs in a biological sample from a subject, allowing for earlier and more sensitive identification of liver fibrosis or liver disease than traditional methods.
The background identifies liver fibrosis as the key pathological feature of most chronic liver diseases, characterized by chronic inflammation and excessive accumulation of extracellular matrix components, leading to severe complications including cirrhosis and liver failure. Liver fibrosis arises from diverse causes such as viral infections, alcoholism, obesity, and exposure to toxic chemicals, posing a significant global health problem. Current diagnostics rely heavily on liver biopsy, which is invasive and prone to sampling errors and observer variability. Non-invasive tests like FibroSure lack sensitivity and specificity for early-stage liver fibrosis. Additionally, there is a critical need for improved methodologies to identify hepatotoxicity early in drug development to prevent costly failures.
The disclosed innovations address these problems by providing molecular assays focused on differential gene expression profiles that correlate with liver fibrosis progression or regression. The invention leverages panels of specific genes and optionally corresponding proteins, peptides, and gene regulators, detectable in non-invasively obtained biological samples like blood or serum, to diagnose liver disease earlier and with higher accuracy. Further, the methods and kits facilitate identification of hepatotoxic compounds in drug development, potentially improving safety assessments and reducing drug development costs.
Claims Coverage
The patent includes one independent claim, covering an array comprising immobilized oligonucleotides specific for genes associated with liver fibrosis diagnosis.
Array comprising oligonucleotides specific to liver fibrosis-associated genes
An array with a substrate supporting twenty-five or more target oligonucleotides and no more than seventy-four total, each specifically hybridizable to mRNA, cDNA, or miRNA corresponding to different genes selected from a defined group of genes associated with liver fibrosis, including mammalian orthologs.
Labelling of oligonucleotides
The array's oligonucleotides are labelled with detectable labels, which can be directly detectable or indirectly labelled with biotin, with streptavidin-conjugated phycoerythrin bound to the biotin.
Immobilization via capture probes
Oligonucleotides on the array are immobilized on the substrate through binding with capture probes, which may themselves be directly or indirectly immobilized.
Diagnostic kit comprising the array
A diagnostic kit for liver disease comprises the disclosed array with the immobilized oligonucleotides specific for liver fibrosis-associated genes.
Methods of contacting biological samples with the array
Methods are provided for contacting a biological sample from a mammalian subject with the disclosed array to detect differential gene expression indicative of liver disease, where the sample may comprise cells, mRNA, or cDNA.
The claims cover a diagnostic array and associated kits specifically designed with immobilized oligonucleotides targeting a panel of genes indicative of liver fibrosis, including labeling and immobilization features, and methods of using such arrays for analyzing biological samples to diagnose liver disease.
Stated Advantages
Allows earlier identification of liver fibrosis or liver disease than existing diagnostic methods.
Enables non-invasive diagnosis of liver fibrosis using biological samples such as blood or serum instead of invasive liver biopsy.
Improves sensitivity and specificity in detection of early-stage liver fibrosis compared to current clinical tests.
Reduces the need for board-certified histopathologists in liver fibrosis diagnosis, lowering cost and complexity.
Supports earlier identification of hepatotoxic compounds in drug development, potentially saving significant costs and time.
Facilitates development of commercial diagnostic products such as handheld devices and kits for clinical and research settings.
Documented Applications
Determining progression or regression of liver fibrosis in mammalian subjects, including humans and various animals.
Diagnosing liver disease, including early-stage liver fibrosis, from biological samples such as blood, plasma, serum, urine, or liver biopsy.
Screening compounds to identify hepatotoxicity or efficacy against liver fibrosis in drug development processes.
Treatment of liver disease by administering compounds identified via the disclosed methods that modulate expression of fibrosis-associated genes or proteins.
Use of arrays, kits, and handheld apparatuses in clinical and research settings to detect liver fibrosis through gene expression analysis.
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