Melatonin-based treatment and diagnosis of bile duct disease
Inventors
Alpini, Gianfranco • DeMorrow, Sharon • Glaser, Shannon
Assignees
US Department of Veterans Affairs • Baylor Scott and White Health
Publication Number
US-9468670-B2
Publication Date
2016-10-18
Expiration Date
2032-04-02
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Abstract
Methods and composition for a melatonin signaling modulator-based diagnosis and therapy are described. For example, in certain aspects methods for administering an anti-tumor therapy using a melatonin signaling modulator are described. Furthermore, the invention provides compositions and methods for detecting biliary tract disease such as cholangiocarcinoma.
Core Innovation
The invention provides methods and compositions for diagnosing and treating diseases of the biliary tract, particularly cholangiocarcinoma, by modulating melatonin signaling pathways. The treatment method involves administering melatonin signaling modulators to inhibit the proliferation of cholangiocytes, which line the intrahepatic and extrahepatic bile ducts of the liver. The modulators include exogenous expression cassettes for genes in the melatonin synthesis and circadian clock pathways such as AANAT, ASMT, Per1, Bmal1, CLOCK, or melatonin itself. These agents can be delivered alone or in combination with other therapies, including chemotherapy, radiotherapy, immunotherapy, gene therapy, or by modifying exposure of the subject to light or darkness to influence melatonin production.
The problem addressed by the invention arises from the limited therapeutic options available for treating cholangiocarcinoma, a cancer of the biliary mucosa with usually poor prognosis because it is often diagnosed at an advanced stage. Cholangiocarcinoma pathogenesis is linked to chronic biliary proliferation and inflammation, and current diagnosis relies on tumor tissue examination, which is inconvenient for early detection. There is a need for novel diagnostic methods and therapies to manage biliary tract diseases.
By identifying the role of melatonin and circadian clock-related genes in regulating cholangiocyte proliferation and apoptosis, the invention overcomes deficiencies in the art by providing targeted melatonin signaling modulators as a novel therapy. The compositions and methods not only inhibit biliary cell proliferation but also offer diagnostic means by measuring melatonin levels or gene expression in fluid or tissue samples, facilitating early and less invasive detection of biliary tract disease.
Claims Coverage
The claims present five main inventive features focused on methods treating biliary diseases by modulation of melatonin signaling components and specific administration routes and agents.
Use of melatonin signaling modulators to inhibit cholangiocyte proliferation
A method for treating biliary hyperplasia, cholestasis, cholangiopathy, cholangiocarcinoma, primary biliary cirrhosis, or primary sclerosing cholangitis in a subject by administering a pharmaceutically effective amount of one or more agents selected from: an exogenous expression cassette for AANAT; an exogenous expression cassette for ASMT; an exogenous expression cassette for Per1; an exogenous inhibitory nucleic acid or analog targeting Bmal1; an exogenous expression cassette for CLOCK; or melatonin, thereby inhibiting cholangiocyte proliferation.
Treatment of cholangiocarcinoma with melatonin-based agents
Using the foregoing method specifically when the condition is cholangiocarcinoma, applying the melatonin signaling modulators to inhibit tumor growth.
Injection of melatonin or melatonin analog directly into the bile duct
A method for treating a subject known or suspected to have biliary diseases by injecting a composition comprising melatonin or a melatonin analog directly into the bile duct of the subject.
Use of agents decreasing AANAT activity or expression to treat specific bile duct diseases
A method of treating bile duct diseases such as liver transplant, drug-induced ductopenia, congenital ductopenia, obstruction, infection, or gall stones by administering agents that decrease the activity or expression of AANAT in the subject.
Selection of miRNAs as agents to decrease AANAT activity or expression
The agents that decrease activity or expression of AANAT include Coenzyme A-S-acetyltryptamine, siRNA, miRNA, or small molecules, with specific miRNAs including miRNA-17, miRNA-19, miRNA-34, miRNA-125b, miRNA-132, miR-4279, miR-875-3p, miR-1299, miR-626, miR-483-5p, miR-542-5p, and others (including multiple hsa-miRs).
The claims cover therapeutic methods using selected melatonin signaling modulators and administration routes to treat biliary tract diseases by inhibiting cholangiocyte proliferation or modulating AANAT activity, including direct bile duct administration and specific nucleic acid agents such as miRNAs.
Stated Advantages
Melatonin signaling modulators inhibit cholangiocyte proliferation and cholangiocarcinoma growth.
The compositions provide a novel therapeutic approach for diseases with limited current treatment options.
Diagnostic methods using melatonin and gene expression levels allow earlier and less invasive detection of biliary tract diseases.
Combination with other therapies and modulation of light exposure enhances therapeutic efficacy.
Documented Applications
Diagnosis of biliary tract diseases such as cholangiocarcinoma by measuring melatonin levels or melatonin signaling modulator gene expression in bile or tissue samples.
Treatment of biliary hyperplasia, cholestasis, cholangiopathy, cholangiocarcinoma, primary biliary cirrhosis, and primary sclerosing cholangitis by administering melatonin signaling modulators.
Direct injection of melatonin or melatonin analog into the bile duct to treat biliary tract diseases.
Use of agents that decrease AANAT activity or expression to treat bile duct diseases including liver transplant complications, ductopenia, obstruction, infection, or gall stones.
Combination therapies with chemotherapy, radiotherapy, immunotherapy, gene therapy, or surgery along with modulation of light exposure for treatment enhancement.
Use of miRNAs and nucleic acid inhibitors as therapeutic agents targeting melatonin synthesis pathways in cholangiocytes.
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